Sodium nitrite-containing pharmaceutical compositions

ABSTRACT

Provided herein are pharmaceutically acceptable sodium nitrite and pharmaceutical compositions thereof. Also provided herein are methods for determining the total non-volatile organic carbon in a sodium nitrite-containing sample. Further provided herein are methods for producing pharmaceutically acceptable sodium nitrite. Still further provided herein are methods of treatment comprising the administration of pharmaceutically acceptable sodium nitrite.

This application is a continuation of U.S. patent application Ser. No.15/973,659, filed May 8, 2018, which is a continuation of U.S. patentapplication Ser. No. 15/599,617, filed May 19, 2017, now U.S. Pat. No.10,251,910, issued Apr. 9, 2019, which is a continuation of U.S. patentapplication Ser. No. 15/249,746, filed Aug. 29, 2016, now U.S. Pat. No.9,687,505, issued Jun. 27, 2017, which is a continuation of U.S. patentapplication Ser. No. 14/547,255, filed Nov. 19, 2014, now U.S. Pat. No.9,597,354, issued Mar. 21, 2017, which is a continuation of U.S. patentapplication Ser. No. 14/042,783, filed Oct. 1, 2013, now U.S. Pat. No.8,920,852, issued Dec. 30, 2014, which is a divisional of U.S. patentapplication Ser. No. 12/703,448, filed Feb. 10, 2010, now U.S. Pat. No.8,568,793, issued Oct. 29, 2013, which claims the benefit of U.S.Provisional Application No. 61/151,820, filed Feb. 11, 2009 and U.S.Provisional Application No. 61/224,021, filed Jul. 8, 2009, each ofwhich is incorporated by reference herein in its entirety.

FIELD

Provided herein are pharmaceutically acceptable sodium nitrite andpharmaceutical compositions thereof. Also provided herein are methodsfor determining the total non-volatile organic carbon in a sodiumnitrite-containing sample. Further provided herein are methods forproducing pharmaceutically acceptable sodium nitrite. Still furtherprovided herein are methods of treatment comprising the administrationof pharmaceutically acceptable sodium nitrite.

BACKGROUND

Sodium nitrite has numerous applications, such as uses as a foodadditive and a pharmaceutical ingredient. Even though thousands ofmetric tons of sodium nitrite are produced annually, only a fewkilograms are utilized pharmaceutically for the production of sodiumnitrite injection as currently indicated as a treatment for cyanidepoisoning. It has been reported that sodium nitrite is an effectivetreatment for hydrogen sulfide poisoning (Hall and Rumack, Vet HumanToxicol. 1997, 39, 152-154). It has been recently reported that sodiumnitrite is an effective vasodilator, which may be used to treat manyconditions, including heart attack, stroke, sickle cell anemia,respiratory diseases, and bacterial, viral or fungal infections (WO2005/004884, WO 2005/007173, U.S. Patent Application Publication Nos.2004/0105898, 2005/0036949, and 2008/0260865, the disclosure of each ofwhich is incorporated herein by reference in its entirety). It has alsobeen recently reported that sodium nitrite augments angiogenesis andarteriogenesis, which may be used to treat ischemic conditions includingangina and claudication. (Kumar et al, Proc. Natl. Acad. Sci. USA 2008,105, 7540-7545). Sodium nitrite is also useful in connection withreducing the risk of hospital-acquired infections, such as nocosomialinfections, originating from the insertion of medical devices, such ascatheters (U.S. Patent Application Publication No. 2007/0239107, thedisclosure which is incorporated herein by reference in its entirety).

The manufacture of pharmaceutical products in the United States isregulated by the Food and Drug Administration (FDA). Since the passageof the Federal Food Drug and Cosmetic Act in 1938, the FDA has requirednew pharmaceutical products and their corresponding active ingredientsto be manufactured in accordance with the exacting requirements of“pharmaceutical grade” Good Manufacturing Practices as detailed in theUnited States Code of Federal Regulations 21 CFR 211. Because of therelatively small quantity of sodium nitrite that is currently used toformulate pharmaceutical products, no raw material supplier presentlymanufactures sodium nitrite in accordance with “pharmaceutical grade”Good Manufacturing Practices.

In addition to regulating manufacturing practices, the FDA establishesstringent quality specifications for each new pharmaceutical product andits corresponding active ingredients. A pharmaceutical product isclassified as “new” if it was introduced to the market after the passageof the Food Drug and Cosmetic Act in 1938. As mandated in this Act, theFDA requires a new pharmaceutical product and its active ingredients tobe manufactured in accordance with “pharmaceutical grade” GoodManufacturing Practices and to meet applicable quality specifications.When the Food Drug and Cosmetic Act was enacted in 1938, pharmaceuticalsthat were already on the market were classified as “grandfathered drugs”and were permitted to remain on the market without formal FDA approvalif the product and its labeling remain unchanged. Any change to theproduct or its labeling would cause the “grandfathered drug” to become a“new” drug that is subject to FDA-imposed regulations and qualitystandards. Currently available sodium nitrite injection that is labeledsolely for use as a treatment of cyanide poisoning is a “grandfatheredmedication”. Consequently, the product formulation and correspondingquality specifications have remain unchanged for decades.

In anticipation of the receipt of a New Drug Application for a sodiumnitrite pharmaceutical product, the FDA recently announced that sodiumnitrite raw material for a new pharmaceutical product must bemanufactured in accordance with “pharmaceutical grade” GoodManufacturing Practices and it must conform to a new set of qualityspecifications. This new set of quality specifications is more expansiveand stringent than the existing quality specifications. Currentlyavailable sodium nitrite raw material does not meet the new set of FDAquality standards and is unsuitable for use in the formulation of a newpharmaceutical product. Consequently, there is a clear and unmet needfor purified sodium nitrite raw material that is manufactured inaccordance with “pharmaceutical grade” Good Manufacturing Practices andthat meets the new set of quality specifications in order to translaterecent nitrite-related research discoveries into FDA-approved clinicaltherapies.

Another hurdle in developing pharmaceutical grade sodium nitrite is thelack of an effective analytical method to determine total non-volatileorganic carbon in a sodium nitrite-containing sample, which is one ofthe new FDA-imposed quality standards. The conventional method for totalnon-volatile organic carbon determination requires that any inorganiccarbon must be removed before measuring the organic carbon content in asample. This is typically achieved by adding acid. At low pH, theinorganic carbon is converted to carbon dioxide, which is then purgedfrom the sample. The sample is then routed to a combustion chamber witha catalyst and a temperature of approximately 680° C. to convert organiccarbon to carbon dioxide. The quantity of carbon dioxide thus producedis then determined using an infrared detector. However, thisconventional method cannot be used to analyze a sodiumnitrite-containing sample. Sodium nitrite explodes when exposed totemperatures in excess of 538° C. Also, sodium nitrite is converted intonitric oxide when exposed to an acid, and the nitric oxide thus formedmay pass into the detector along with carbon dioxide, interfere with thedetection, and produce false signals. Furthermore, sodium nitrite mayprecipitate during the analysis. Deposits of sodium nitrite salt on thecatalyst can foul the catalyst and preclude complete combustion.Deposits of sodium nitrite salt on the optics can also decrease thelight intensity of the radiation source. Therefore, there is also a needfor an analytical method for determining total non-volatile organiccarbon in a sodium nitrite-containing sample.

Another hurdle in developing pharmaceutical grade sodium nitrite is thepresence of anti-caking material in non-pharmaceutical grade sodiumnitrite. Sodium nitrite is hygroscopic. To prevent the absorption ofwater over time and to facilitate industrial usage, manufacturers ofnon-pharmaceutical grade sodium nitrite generally add anti-cakingmaterial with surfactant characteristics, such as sodium alkylnaphthalene sulfonate. Even if a manufacturer of non-pharmaceuticalgrade sodium nitrite that contains an anti-caking agent produces a batchof sodium nitrite without the addition of an anti-caking agent, tracequantities of the anti-caking agent that exceed the new FDA-imposedquality standards may be present. Therefore, any anti-caking material insodium nitrite must be detected, quantified, and limited in order toproduce pharmaceutical grade sodium nitrite.

SUMMARY OF THE DISCLOSURE

Provided herein is sodium nitrite which contains no greater than about0.02% by weight of sodium carbonate and/or no greater than about 10 ppm(0.001% by weight) of an anti-caking agent.

Also provided herein are pharmaceutical compositions, which comprisesodium nitrite and a pharmaceutically acceptable excipient, wherein thesodium nitrite contains no greater than about 0.02% by weight of sodiumcarbonate or no greater than about 10 ppm (0.001% by weight) of ananti-caking agent.

Also provided herein are methods of determining the total non-volatileorganic carbon in a sodium nitrite-containing sample, which comprisesthe steps of: a) adding an inorganic acid in a predetermined amount toan aqueous sample solution that contains sodium nitrite; b) adding anoxidizer in a predetermined amount to the sample solution; and c)converting the organic carbon in the sample solution into carbon dioxideunder a supercritical water oxidation condition; wherein the finalamount of the inorganic acid is no less than 2% of the final volume ofthe sample solution or the final amount of the oxidizer is no less than20% of the final volume of the sample solution.

Also provided herein are methods for preparing the pharmaceuticallyacceptable sodium nitrite, which comprises the steps of: a) contactingnon-pharmaceutical grade sodium nitrite (wherein non-pharmaceuticalgrade sodium nitrite includes, but is not limited to, food grade sodiumnitrite) with a first solvent at a first temperature; b) heating themixture to a second temperature; c) cooling the mixture to a thirdtemperature; d) contacting the mixture with activated carbon; e) coolingthe mixture to a fourth temperature; and f) contacting the mixture witha second solvent.

Also provided herein are methods for treating an acute poisoning,including, but not limited to, cyanide poisoning and hydrogen sulfidepoisoning, which comprises administering to a subject a therapeuticallyeffective amount of sodium nitrite provided herein.

Also provided herein are methods for treating a cardiovascular diseaseor a condition associated with the cardiovascular system, including, butnot limited to, high blood pressure, pulmonary hypertension, angina,claudication, cerebral vasospasm, and tissue ischemia-reperfusioninjury, which comprises administering to a subject a therapeuticallyeffective amount of sodium nitrite provided herein.

Also provided herein are methods for treating a respiratory disease or acondition associated with the tracheo-pulmonary system, including, butnot limited to, cystic fibrosis, pulmonary tuberculosis, mycoticpneumonia, bacterial pneumonia, viral pneumonia, pulmonary abscess,pulmonary hypertension, pulmonary embolism, and pulmonary vasospasm,which comprises administering to a subject a therapeutically effectiveamount of sodium nitrite provided herein.

Also provided herein are methods for treating a dermatological diseaseor a condition associated with the skin, including, but not limited to,bacterial infection of the skin, mycotic infection of the skin, viralinfection of the skin, mycotic infection of the nails, bacterialinfection of the nails, viral infection of the nails, mycotic infectionof the nailbeds, bacterial infection of the nailbeds, viral infection ofthe nailbeds, psoriasis, scleroderma, inflammation of the skin,inflammation of the nails, and inflammation of the nailbeds, whichcomprises administering to a subject a therapeutically effective amountof sodium nitrite provided herein.

Also provided herein are methods for treating, preventing or reducingthe risk of hospital-acquired infections, such as nocosomial infections,which can originate from the insertion of a device (e.g., a medicaldevice) and/or the use of a device in the body.

DETAILED DESCRIPTION

To facilitate understanding of the disclosure set forth herein, a numberof terms are defined below.

Generally, the nomenclature used herein and the laboratory procedures ininorganic chemistry, analytical chemistry, organic chemistry, medicinalchemistry, and pharmacology described herein are those well known andcommonly employed in the art. Unless defined otherwise, all technicaland scientific terms used herein generally have the same meaning ascommonly understood by one of ordinary skill in the art to which thisdisclosure belongs. In the event that there is a plurality ofdefinitions for a term used herein, those in this section prevail unlessstated otherwise.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat,or mouse. The terms “subject” and “patient” are used interchangeablyherein in reference, for example, to a mammalian subject, such as ahuman subject. In one embodiment, the subject has or is at risk for adisease, disorder or condition provided herein. In another embodiment,the patient has or is at risk for a disease, disorder or conditionwherein the disease, disorder or condition, or a symptom thereof, can betreated, prevented or ameliorated by the administration of sodiumnitrite.

The term “host” refers to a unicellular or multicellular organism inwhich a virus can replicate, including, but not limited to, a cell, cellline, and animal, such as human.

The terms “treat,” “treating,” and “treatment” are meant to includealleviating or abrogating a disorder, disease, or condition, or one ormore of the symptoms associated with the disorder, disease, orcondition; or alleviating or eradicating the cause(s) of the disorder,disease, or condition itself.

The terms “prevent,” “preventing,” and “prevention” are meant to includea method of delaying and/or precluding the onset of a disorder, disease,or condition, and/or its attendant symptom(s); barring a subject fromacquiring a disease; or reducing a subject's risk of acquiring adisorder, disease, or condition.

The term “therapeutically effective amount” is meant to include theamount of a compound that, when administered, is sufficient to preventdevelopment of, or alleviate to some extent, one or more of the symptomsof the disorder, disease, or condition being treated. The term“therapeutically effective amount” also refers to the amount of acompound that is sufficient to elicit the biological or medical responseof a cell, tissue, system, animal, or human, which is being sought by aresearcher, veterinarian, medical doctor, or clinician.

The term “pharmaceutically acceptable carrier,” “pharmaceuticallyacceptable excipient,” “physiologically acceptable carrier,” or“physiologically acceptable excipient” refers to apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, excipient, solvent, or encapsulatingmaterial. In one embodiment, each component is “pharmaceuticallyacceptable” in the sense of being compatible with the other ingredientsof a pharmaceutical formulation, and suitable for use in contact withcells, tissues, or organs of humans and animals without excessivetoxicity, irritation, allergic response, immunogenicity, or otherproblems or complications, commensurate with a reasonable benefit/riskratio. See, Remington: The Science and Practice of Pharmacy, 21stEdition, Lippincott Williams & Wilkins: Philadelphia, Pa., 2005;Handbook of Pharmaceutical Excipients, 5th Edition, Rowe et al., Eds.,The Pharmaceutical Press and the American Pharmaceutical Association:2005; and Handbook of Pharmaceutical Additives, 3rd Edition, Ash and AshEds., Gower Publishing Company: 2007; Pharmaceutical Preformulation andFormulation, Gibson Ed., CRC Press LLC: Boca Raton, Fla., 2004.

The term “about” or “approximately” means an acceptable error for aparticular value as determined by one of ordinary skill in the art,which depends in part on how the value is measured or determined. Incertain embodiments, the term “about” or “approximately” means within 1,2, 3, or 4 standard deviations. In certain embodiments, the term “about”or “approximately” means within 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%,2%, 1%, 0.5%, or 0.05% of a given value or range. In certainembodiments, it is contemplated that the values preceded by the term“about” or “approximately” are exact.

The terms “active ingredient” and “active substance” refer to acompound, which is administered, alone or in combination with one ormore pharmaceutically acceptable excipients, to a subject for treating,preventing, or ameliorating one or more symptoms of a condition,disorder, or disease. As used herein, “active ingredient” and “activesubstance” may be an optically active isomer of a compound describedherein.

The terms “drug,” “therapeutic agent,” and “chemotherapeutic agent”refer to a compound, or a pharmaceutical composition thereof, which isadministered to a subject for treating, preventing, or ameliorating oneor more symptoms of a condition, disorder, or disease.

The term “anti-solvent” refers to a liquid that is added to a solvent toreduce the solubility of a compound in that solvent, resulting inprecipitation or crystallization of the compound.

The term “sodium phosphate” refers to sodium dihydrogen phosphate(NaH₂PO₄), disodium hydrogen phosphate (Na₂HPO₄), or trisodium phosphate(Na₃PO₄). In certain embodiments, the sodium phosphate is sodiumdihydrogen phosphate. In certain embodiments, the sodium phosphate isdisodium hydrogen phosphate. In certain embodiments, the sodiumphosphate is trisodium phosphate.

Sodium Nitrite

Provided herein are purified forms of sodium nitrite (NaNO₂), also knownas monosodium salt of nitrous acid. In one embodiment, provided hereinis pharmaceutically acceptable sodium nitrite. In another embodiment,provided herein are forms of sodium nitrite meeting one, more than one,or all FDA standards for sodium nitrite for pharmaceutical use.

In one embodiment, the pharmaceutically acceptable sodium nitrite iswhite to off-white solid.

In one embodiment, the pharmaceutically acceptable sodium nitrite has apositive identification test for sodium determined according to method<191> in USP XXXII (2009).

In one embodiment, the pharmaceutically acceptable sodium nitrite has apositive identification test for nitrite determined according to method<191> in USP XXXII (2009).

In one embodiment, the sodium nitrite provided herein contains no lessthan about 97% by weight and/or no greater than about 101% by weight ofsodium nitrite. In certain embodiments, the amount of sodium nitrite inthe sodium nitrite provided herein is determined according to USPcolormetric assay (USP XXXII (2009)). In certain embodiments, the amountof sodium nitrite in the sodium nitrite provided herein is determined byan ion chromatography. In certain embodiments, the amount of sodiumnitrite in the sodium nitrite provided herein is determined by an ionchromatography is coupled with suppressed conductivity detection asdescribed herein.

In another embodiment, the sodium nitrite provided herein has a pHbetween about 8 to about 9 when measured in a 10% solution at 25° C. Incertain embodiments, the pH of the sodium provided herein is measuredusing a pH meter. In certain embodiments, the pH of the sodium providedherein is determined according to Method 791 in USP XXXII (2009).

In yet another embodiment, the sodium nitrite provided herein has a losson drying of no greater than about 0.25% by weight. In certainembodiments, the loss on drying of the sodium nitrite provided herein isquantitated according to Method 731 in USP XXXII (2009).

In yet another embodiment, the sodium nitrite provided herein has watercontent of no greater than about 0.5% by weight. In certain embodiments,the water content in the sodium nitrite provided herein is determined byKarl Fischer method. In certain embodiments, the water content in thesodium nitrite provided herein is quantitated according to Method 921 inUSP XXXII (2009).

In yet another embodiment, the heavy metal content in the sodium nitriteprovided herein is no greater than about 10 ppm of a heavy metal. Theheavy metal content in the sodium nitrite provided herein is determinedaccording to Method 231 in USP XXXII (2009).

In yet another embodiment, the sodium nitrite provided herein containsno greater than about 0.4% by weight of sodium nitrate. In certainembodiments, the amount of sodium nitrate in the sodium nitrite providedherein is determined by an ion chromatography method in coupled withsuppressed conductivity detection as described herein.

In yet another embodiment, the sodium nitrite provided herein containsno greater than about 0.02% by weight of sodium carbonate. In certainembodiments, the amount of sodium carbonate in the sodium nitriteprovided herein is determined by mixing the sample with an acid toconvert carbonate to carbon dioxide and venting the carbon dioxide to anondispersive infrared detector for measurement.

In yet another embodiment, the sodium nitrite provided herein containsno greater than about 0.005% by weight of insoluble matter. In certainembodiments, the amount of insoluble material in the sodium nitriteprovided herein is determined by dissolving 10 grams of the sodiumnitrite provided herein in 100 mL of water, the solution is heated toboiling for 1 hour, the solution is filtered, washed with hot water,dried, cooled in a desiccator, and weighed.

In yet another embodiment, the sodium nitrite provided herein containsno greater than about 0.005% by weight of chloride. In certainembodiments, the chloride content in the sodium nitrite provided hereinis determined according to Method 221 in USP XXXII (2009).

In yet another embodiment, the sodium nitrite provided herein containsno greater than about 0.01% by weight of sulfate. In certainembodiments, the sulfate content in the sodium nitrite provided hereinis determined according to Method 221 in USP XXXII (2009).

In yet another embodiment, the sodium nitrite provided herein containsno greater than about 0.001% by weight of iron. In certain embodiments,the iron content in the sodium nitrite provided herein is determinedusing inductively coupled plasma mass spectrometry (ICP-MS). In certainembodiments, the iron content in the sodium nitrite provided herein isdetermined using inductively coupled plasma-optical emissionspectroscopy (ICP-OES). In certain embodiments, the iron content in thesodium nitrite provided herein is determined according to Method 241 inUSP XXXII (2009).

In yet another embodiment, the sodium nitrite provided herein containsno greater than about 0.01% by weight of calcium. In certainembodiments, the calcium content in the sodium nitrite provided hereinis determined using ICP-MS. In certain embodiments, the calcium contentin the sodium nitrite provided herein is determined using flame emissionspectrometry (FES).

In yet another embodiment, the sodium nitrite provided herein containsno greater than about 0.005% by weight of potassium. In certainembodiments, the potassium content in the sodium nitrite provided hereinis determined using ICP-MS. In certain embodiments, the potassiumcontent in the sodium nitrite provided herein is determined using FES.

In yet another embodiment, the sodium nitrite provided herein containsno greater than about 10 ppm, no greater than about 100 ppm, no greaterthan about 500 ppm, no greater than about 1000 ppm, or no greater than5000 ppm of ethanol. In certain embodiments, the content of organicvolatile impurities is determined according to Method 467 in USP XXXII(2009).

In yet another embodiment, the sodium nitrite provided herein containsno greater than about 10 ppm, no greater than about 100 ppm, no greaterthan about 500 ppm, no greater than about 1000 ppm, or no greater than3000 ppm of methanol. In certain embodiments, the content of organicvolatile impurities is determined according to Method 467 in USP XXXII(2009).

In yet another embodiment, the sodium nitrite provided herein containstotal non-volatile organic carbon of no greater than about 2.5 ppm, nogreater than about 6 ppm, no greater than about 8 ppm, no greater thanabout 10 ppm, no greater than about 20 ppm, no greater than about 25ppm, or no greater than about 50 ppm. In certain embodiments, the sodiumnitrite provided herein contains total non-volatile organic carbon(NVOC) or equivalent non-purgable organic carbon (NPOC) of no greaterthan about 10 ppm. In certain embodiments, the sodium nitrite providedherein contains total non-volatile organic carbon of no greater thanabout 7.9 ppm. In certain embodiments, the sodium nitrite providedherein contains total non-volatile organic carbon of no greater thanabout 5.6 ppm. In certain embodiments, the total non-volatile organiccarbon in the sodium nitrite provided herein is determined using methodsdescribed herein.

In yet another embodiment, the sodium nitrite provided herein containsno greater than about 0.05 ppm of mercury. In certain embodiments, themercury content in the sodium nitrite provided herein is determinedusing ICP-MS. In certain embodiments, the mercury content in the sodiumnitrite provided herein is determined using ICP-OES. In certainembodiments, the mercury content in the sodium nitrite provided hereinis determined according to Method 261 in USP XXXII (2009).

In yet another embodiment, the sodium nitrite provided herein containsno greater than about 2 ppm of aluminum. In yet another embodiment, thesodium nitrite provided herein contains no greater than about 0.2 ppm ofaluminum. In certain embodiments, the aluminum content in the sodiumnitrite provided herein is determined using ICP-MS. In certainembodiments, the aluminum content in the sodium nitrite provided hereinis determined using ICP-OES. In certain embodiments, the aluminumcontent in the sodium nitrite provided herein is determined according toMethod 206 in USP XXXII (2009).

In yet another embodiment, the sodium nitrite provided herein containsno greater than about 3 ppm of arsenic. In yet another embodiment, thesodium nitrite provided herein contains no greater than about 1 ppm ofarsenic. In certain embodiments, the arsenic content in the sodiumnitrite provided herein is determined using ICP-MS. In certainembodiments, the arsenic content in the sodium nitrite provided hereinis determined using ICP-OES. In certain embodiments, the arsenic contentin the sodium nitrite provided herein is determined according to Method211 in USP XXXII (2009).

In yet another embodiment, the sodium nitrite provided herein containsno greater than about 10 ppm (0.001% by weight) of an anti-caking agent.In certain embodiments, the anti-caking agent is sodiumalkyl-naphthalene sulfonate. In certain embodiments, the amount ofsodium alkyl-naphthalene sulfonate in the sodium nitrite provided hereinis quantitated using mass spectrometry and liquid chromatography methodas described herein.

In yet another embodiment, the sodium nitrite provided herein containsno greater than about 0.003% by weight of selenium. In certainembodiments, the selenium content in the sodium nitrite provided hereinis determined using ICP-MS. In certain embodiments, the selenium contentin the sodium nitrite provided herein is determined using ICP-OES. Incertain embodiments, the selenium content in the sodium nitrite providedherein is determined according to Method 291 in USP XXXII (2009).

In yet another embodiment, the total aerobic count of microbial load inthe sodium nitrite provided herein is no greater than about 100 CFU/g.The total aerobic count of microbial load in the sodium nitrite providedherein is quantitated according to Method 61 in USP XXXII (2009).

In yet another embodiment, the total yeast and mold count in the sodiumnitrite provided herein is no greater than about 20 CFU/g. The totalyeast and mold count in the sodium nitrite provided herein isquantitated according to Method 61 in USP XXXII (2009).

In yet another embodiment, the sodium nitrite provided herein containsno greater than about 0.25 EU/mg of bacterial endotoxins. The amount ofbacterial endotoxins in the sodium nitrite provided herein isquantitated according to Method 85 in USP XXXII (2009).

In yet another embodiment, the sodium nitrite provided herein containsless than about 0.1 ppm of sodium phosphate. In certain embodiments, thesodium nitrite provided herein contains does not contain a detectableamount of sodium phosphate. In certain embodiments, the sodium phosphateis disodium hydrogen phosphate. In certain embodiments, the sodiumphosphate is trisodium phosphate.

In yet another embodiment, the sodium nitrite provided herein ischaracterized by one or more of the following:

containing no less than about 97% by weight and/or no greater than about101% by weight of sodium nitrite;

having a positive identification test for sodium;

having a positive identification test for thiosulfate;

having a pH between about 8 to about 9 when measured in a 10% solutionat 25° C.;

having a loss on drying of no greater than about 0.25% or about 0.01% byweight;

having water content of no greater than about 0.5% by weight;

having heavy metal content of no greater than about 10 ppm;

containing no greater than about 0.4% by weight of sodium nitrate;

containing no greater than about 0.02%, about 0.01% or about 0.001% byweight of sodium carbonate;

containing no greater than about 0.005% or about 0.001% by weight ofinsoluble matter;

containing no greater than about 0.005% by weight of chloride;

containing no greater than about 0.01% by weight of sulfate;

containing no greater than about 0.001% by weight of iron;

containing no greater than about 0.01% by weight of calcium;

containing no greater than about 0.005% or about 0.001% by weight ofpotassium;

containing no greater than about 0.1% by weight ethanol or no greaterthan about 10 ppm, no greater than about 100 ppm, no greater than about500 ppm, no greater than about 1000 ppm, or no greater than 5000 ppm ofethanol;

containing no greater than about 10 ppm, no greater than about 100 ppm,no greater than about 500 ppm, no greater than about 1000 ppm, or nogreater than 3000 ppm of methanol;

having total non-volatile organic carbon or equvalent of no greater thanabout 2.5 ppm, no greater than about 5.6 ppm, no greater than about 6ppm, no greater than about 7.9 ppm, no greater than about 8 ppm, nogreater than about 10 ppm, no greater than about 20 ppm, no greater thanabout 25 ppm, or no greater than about 50 ppm; and in one embodiment, nogreater than about 10 ppm;

containing no greater than about 0.05 ppm of mercury;

containing no greater than about 2 ppm or 0.2 ppm of aluminum;

containing no greater than about 3 ppm or about 1 ppm of arsenic;

containing no greater than about 10 ppm or about 0.001% by weight of ananti-caking agent;

containing no greater than about 0.003% or about 0.001% by weight ofselenium (ICP-OES or equivalent);

having a total aerobic count of microbial load of no greater than about100 CFU/g;

having a total yeast and mold count of no greater than about 20 CFU/g;

containing no greater than about 0.25 EU/mg or about 0.018 EU/mg ofbacterial endotoxins; and containing no greater than about 0.1 ppm ofsodium phosphate.

In one embodiment, provided herein is sodium nitrite having one or moreof the characteristics referenced herein produced by a process providedherein. In one embodiment, provided herein is sodium nitrite having oneor more of the characteristics set forth in Table 1.

Preparation of Sodium Nitrite

Also provided herein are methods for preparing the pharmaceuticallyacceptable sodium nitrite, which comprises the steps of: a) contactingnon-pharmaceutical grade sodium nitrite (wherein non-pharmaceuticalgrade sodium nitrite includes, but is not limited to, food grade sodiumnitrite) with a first solvent at a first temperature; b) heating themixture to a second temperature; c) cooling the mixture to a thirdtemperature; d) contacting the mixture with activated carbon; e) coolingthe mixture to a fourth temperature; and f) contacting the mixture witha second solvent. In certain embodiments, the method further comprisesan isolation step after one or more of the steps provided herein inwhich the sodium nitrite is isolated under inert atmosphere (e.g., N₂ orAr) by a conventional method, such as filtration or centrifugation,followed by drying (e.g., vacuum oven drying, air drying, or desicatordrying). In one embodiment, the first solvent is a polar solvent, suchas water (including but not limited to water, purified water, utrapurewater, and water for injection). In another embodiment, the secondsolvent is an organic solvent, such as ethyl alcohol.

In certain embodiments, the sodium nitrite is dried under inertatmosphere at an elevated temperature of no greater than the meltingpoint of sodium nitrite. In certain embodiments, the elevatedtemperature is about 60-70° C. or ≤65° C. In particular embodiments, theelevated temperature is about 60° C. or about 65° C.

Suitable solvents for use in the method provided herein include, but arenot limited to, water (including but not limited to water, purifiedwater, utrapure water, and water for injection), methanol, ethanol,isopropanol (IPA), 1-propanol, 2-methoxyethanol, 2-ethoxyethanol,ethyleneglycol, ethyl alcohol, acetone, N,N-dimethylformamide (DMF),N,N-dimethylacetamide, acetonitrile (ACN), dimethyl sulfoxide (DMSO),N-methyl pyrrolindone, tetrahydrofuran (THF), dioxane, acetic acid,trichloroacetic acid, trifluoroacetic acid, and a mixture thereof. Inone embodiment, the solvent is aqueous. In another embodiment, thesolvent is water. In yet another embodiment, the solvent is a mixture ofwater with a water-miscible solvent, including, but not limited to,methanol, ethanol, isopropanol (IPA), 1-propanol, 2-methoxyethanol,2-ethoxyethanol, ethyleneglycol, acetone, N,N-dimethylformamide (DMF),N,N-dimethylacetamide, acetonitrile (ACN), dimethyl sulfoxide (DMSO),N-methyl pyrrolindone, tetrahydrofuran (THF), dioxane, acetic acid,trichloroacetic acid, trifluoroacetic acid, and a mixture thereof.

In certain embodiments, the sodium nitrite is prepared from a solutionor slurry of sodium nitrite in a solvent using conventional methods,including, but not limited to, cooling, chilling, solvent evaporation,or addition of an anti-solvent.

In one embodiment, the method for preparing the sodium nitrite providedherein comprises the steps of: (a) preparing a solution of sodiumnitrite in a solvent at a first temperature under inert atmosphere; and(b) generating sodium nitrite at a second temperature under inertatmosphere. To accelerate the formation of the sodium nitrite, themethod may also comprise a seeding step by seeding the solution withcrystals of sodium nitrite under inert atmosphere, prior to or duringstep (b). In certain embodiments, the method further comprises anisolation and drying step as described herein.

In certain embodiments, the solution of step (a) is prepared as asaturated or nearly saturated solution at the first temperature. Thesaturated or nearly saturated solution is prepared by dissolving asufficient amount of sodium nitrite in the solvent at a temperature thatis higher than the first temperature, such that, when the solution isallowed to cool to the first temperature, a saturated or nearlysaturated solution is obtained. The sufficient amount of sodium nitritecan be estimated based on the solubility of sodium nitrite in thesolvent at the first temperature, which is known in the art or can bedetermined using a method known to a person skilled in the art.

In certain embodiments, the first temperature ranges from roomtemperature to about the boiling point of the solvent employed and nogreater than the melting point of sodium nitrite (about 270° C.). Incertain embodiments, the first temperature ranges from −100 to 100° C.,from about −50 to about 50° C., from about −10 to about 30° C., fromabout 0 to about 30° C., from about 15 to about 30° C. or from about 20to about 30° C. In certain embodiments, the second temperature rangesfrom about 10 to about 110° C., from about 20 to about 100° C., fromabout 20 to about 80° C., from about 20 to about 60° C., from about 20to about 40° C., from about 30 to about 60° C., from about 45 to about55° C., from about 20 to about 30° C. or from about 45 to about 55° C.In certain embodiments, the third temperature ranges from −100 to 100°C., from about −50 to about 50° C., from about −10 to about 30° C., fromabout 0 to about 30° C., from about 15 to about 30° C. or from about 20to about 30° C. In certain embodiments, the fourth temperature rangesfrom −100 to 100° C., from about −50 to about 50° C., from about −10 toabout 30° C., from about 0 to about 20° C., or from about 0 to about 10°C. To maximize the yield and the efficiency of the method providedherein, the third temperature is normally set to be lower than thesecond temperature. In certain embodiments, the first temperature isabout 24 to about 30° C. and the second temperature is about 45 to about55° C. In certain embodiments, the first temperature is about 20 toabout 30° C., the second temperature is about 45 to about 55° C. and thethird temperature is about 20 to about 30° C. In certain embodiments,the first temperature is about 20 to about 30° C., the secondtemperature is about 45 to about 55° C., the third temperature is about20 to about 30° C. and the fourth temperature is about 0 to about 10° C.In certain embodiments, the first temperature is about 25° C., thesecond temperature is about 50° C., the third temperature is about 25°C. and the fourth temperature is about 5° C.

In one embodiment, the sodium nitrite provided herein is obtained byevaporating the solvent from the solution at the second temperature. Thesolvent evaporation can be facilitated by applying heat and/or vacuum tothe solution.

In another embodiment, the sodium nitrite is obtained by cooling thesolution to the fourth temperature.

In yet another embodiment, the sodium nitrite is formed by adding ananti-solvent to the solution at a fourth temperature. Suitableanti-solvents include, but are not limited to, methanol, ethanol,isopropanol (IPA), 1-propanol, 2-methoxyethanol, 2-ethoxyethanol,ethyleneglycol, acetone, N,N-dimethylformamide (DMF),N,N-dimethylacetamide, acetonitrile (ACN), dimethyl sulfoxide (DMSO),N-methyl pyrrolindone, tetrahydrofuran (THF), dioxane, acetic acid,trichloroacetic acid, trifluoroacetic acid, and a mixture thereof.

When two solvents are used as a solvent/anti-solvent pair, sodiumnitrite has a higher solubility in the solvent than in the anti-solvent.Optionally, the solvent and the anti-solvent in a solvent/anti-solventpair are at least partially miscible. In certain embodiments, thesolvent is water. In certain embodiments, the anti-solvent is awater-miscible solvent. In certain embodiments, the anti-solvent isethanol.

In yet another embodiment, the sodium nitrite is formed by adding thesolution to an anti-solvent at the fourth temperature. In oneembodiment, the solvent is water, and the anti-solvent is ethanol.

In certain embodiments, the solution (a) is stirred at room temperatureunder an inert atmosphere for up to 15, 30, 45 or 60 minutes or longer.

In certain embodiments, one or more of the steps provided herein arecarried out under inert atmopshere (e.g., N₂ or Ar).

In certain embodiments, a purification step or a filtering step isperformed between one or more steps provided herein.

In certain embodiments, filtering steps are carrier out using aglass-microfiber filter (e.g., ≤1.6 μm). In other embodiments, filteringsteps are carrier out using an Aurora filter, a Cogeim filter or anEstrella filter.

Other methods known in the art may also be applicable for preparing thepharmaceutically acceptable sodium nitrite provided herein, includingspray drying, roller drying, lyophilization, and melt crystallization.

Methods of Characterization:

1. Determining the Total Non-Volatile Organic Carbon in Sodium Nitrite

Provided herein are methods of determining the total non-volatileorganic carbon in a sodium nitrite-containing sample, which comprise thesteps of: (a) adding an inorganic acid in a predetermined amount to anaqueous sample solution that contains sodium nitrite; (b) adding anoxidizer in a predetermined amount to the sample solution; and (c)converting the organic carbon in the sample solution into carbon dioxideunder a supercritical water oxidation condition; wherein the finalamount of the inorganic acid is no less than about 2% of the finalvolume of the sample solution or the final amount of the oxidizer is noless than about 20% of the final volume of the sample solution.

In one embodiment, the inorganic acid is phosphoric acid. In anotherembodiment, the inorganic acid is 6 N phosphoric acid. In yet anotherembodiment, the final amount of the inorganic acid is no less than about2% and no greater than about 50% of the final volume of the samplesolution. In yet another embodiment, the final amount of the inorganicacid is about 2%, about 3%, about 4%, about 5%, about 6%, about 7%,about 8%, about 9%, about 10%, about 15%, about 20%, about 30%, about40%, or about 50% of the final volume of the sample solution. In yetanother embodiment, the final amount of the inorganic acid is about 6%of the final volume of the sample solution. In still another embodiment,the inorganic acid is 6 N phosphoric acid and the final amount of theinorganic acid is about 6% of the final volume of the sample solution.

In one embodiment, the oxidizer is sodium persulfate. In anotherembodiment, the oxidizer is 30% sodium persulfate solution. In yetanother embodiment, the final amount of the oxidizer is no less thanabout 20% but no greater than about 90% of the final volume of thesample solution. In yet another embodiment, the final amount of theoxidizer is about 20%, about 25%, about 30%, about 35%, about 40%, about45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%,about 80%, or about 90% of the final volume of the sample solution. Inyet another embodiment, the final amount of the oxidizer is about 45% ofthe final volume of the sample solution. In still another embodiment,the oxidizer is 30% sodium persulfate solution and the final amount ofoxidizer is about 45% of the final volume of the sample solution.

In certain embodiments, the organic carbon in the sodiumnitrite-containing sample is oxidized according any SCWO processes knownin the art, such as those disclosed in U.S. Pat. Nos. 2,944,396,4,543,190, 5,387,398, 5,405,533, 5,501,799, 5,560,822, 5,804,066,6,054,057, 6,056,883, 6,238,568, 6,519,926, 6,576,185, 6,709,602, and6,773,581, the disclosure of each of which is incorporated herein byreference in its entirety. In certain embodiments, the SCWO process iscarried out in an InnovOx laboratory TOC Analyzer (GE AnalyticalInstruments, Inc., Boulder, Colo.). Supercritical water oxidation (SCWO)processes take advantage of the unique properties of water at conditionsnear and beyond the thermodynamic critical point of water (375° C. and218 atm). The increased pressure under supercritical water oxidationconditions dramatically increases the efficiency of the oxidationprocess by converting the organic carbon in the sodiumnitrite-containing sample into carbon dioxide.

In certain embodiments, the sodium nitrite-containing sample solution isprepared by adding 5.0 g of a sodium nitrite-containing sample intowater to make 100 mL solution. In certain embodiments, the water used inthe method has total organic carbon of no greater than 0.10 ppm.

In certain embodiments, the method further comprises the step ofdetermining the amount of carbon dioxide formed after oxidation. Incertain embodiments, the carbon dioxide is quantitated using an infrareddetector. In certain embodiments, the carbon dioxide is quantitatedusing a nondispersive infrared detector.

2. Quantitation of Nitrite and Nitrate in Sodium Nitrite

In certain embodiments, provided herein is a method of quantitatingnitrite and nitrate in a sodium nitrite-containing sample, whichcomprises the steps of: (a) separating nitrite and nitrate by ionchromatography; and (b) quantitating the individual amounts of nitriteand nitrate using suppressed conductivity detection. In certainembodiments, the ion chromatography is performed isocratically. Incertain embodiments, the aqueous mobile phase contains sodium carbonateand sodium bicarbonate. In certain embodiments, the aqueous mobile phasecontains 2.7 mM sodium carbonate and 0.3 mM sodium bicarbonate.

3. Quantitation of Alkyl Naphthalene Sulfonates in Sodium Nitrite

In certain embodiments, provided herein is a method of quantitatingalkyl naphthalene sulfonates in a sodium nitrite-containing sample,which comprises quantitating the alkyl naphthalene sulfonates with massspectrometer and liquid chromatography.

4. Quantitation of Nitrogen Oxide Impurities in Sodium Nitrite

In certain embodiments, provided herein is a method of quantitatingnitrogen oxide impurities in a sodium nitrite-containing sample, whichcomprises quantitating the nitrogen oxide impurities using nitrogenoxide (NO_(x)) electrode.

Pharmaceutical Compositions

Provided herein are pharmaceutical compositions comprising the sodiumnitrite provided herein as an active ingredient, alone or in combinationwith a pharmaceutically acceptable vehicle, carrier, diluent, orexcipient, or a mixture thereof.

The compound provided herein may be administered alone, or incombination with one or more other active ingredients. Thepharmaceutical compositions that comprise the sodium nitrite providedherein may be formulated in various dosage forms for oral, parenteral,and topical administration. The pharmaceutical compositions may also beformulated as modified release dosage forms, including delayed-,extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-and fast-, targeted-, programmed-release, and gastric retention dosageforms. These dosage forms can be prepared according to conventionalmethods and techniques known to those skilled in the art (see,Remington: The Science and Practice of Pharmacy, supra; Modified-ReleaseDrug Deliver Technology, Rathbone et al., Eds., Drugs and thePharmaceutical Science, Marcel Dekker, Inc.: New York, N.Y., 2003; Vol.126).

In one embodiment, the pharmaceutical compositions are provided in adosage form for oral administration, which comprise the sodium nitriteprovided herein, and one or more pharmaceutically acceptable excipientsor carriers.

In another embodiment, the pharmaceutical compositions are provided in adosage form for parenteral administration, which comprise the sodiumnitrite provided herein, and one or more pharmaceutically acceptableexcipients or carriers.

In yet another embodiment, the pharmaceutical compositions are providedin a dosage form for topical administration, including pulmonaryadministration, which comprise the sodium nitrite provided herein, andone or more pharmaceutically acceptable excipients or carriers.

In one embodiment, the pharmaceutical composition comprises sodiumnitrite provided herein and water. In another embodiment, thepharmaceutical composition comprises about 300 mg of sodium nitriteprovided herein in about 10 mL of water.

In one embodiment, the pharmaceutical composition provided hereinfurther comprises an acid. In certain embodiments, the acid is anorganic acid. In certain embodiments, the acid is an inorganic acid. Incertain embodiments, the acid is acetic acid or ascorbic acid. Incertain embodiments, the sodium nitrite and the acid the pharmaceuticalcomposition provided herein are mixed together when the composition isadministered to a subject. In certain embodiments, the pharmaceuticalcomposition provided herein is administered in or through a medicalinstrument or device (See, U.S. Pat. App. Publ. No. 2007/0239107, thedisclosure of which is incorporated herein by reference in itsentirety).

In certain embodiments, the sodium nitrite in pharmaceutical compositionprovided herein is not acidified (e.g., non-acidified).

The pharmaceutical compositions provided herein may be provided in aunit-dosage form or multiple-dosage form. A unit-dosage form, as usedherein, refers to a physically discrete unit suitable for administrationto a human and animal subject, and packaged individually as is known inthe art. Each unit-dose contains a predetermined quantity of the activeingredient(s) sufficient to produce the desired therapeutic effect, inassociation with the required pharmaceutical carriers or excipients.Examples of a unit-dosage form include an ampoule, syringe, andindividually packaged tablet or capsule. A unit-dosage form may beadministered in fractions or multiples thereof. A multiple-dosage formis a plurality of identical unit-dosage forms packaged in a singlecontainer to be administered in segregated unit-dosage form. Examples ofa multiple-dosage form include a vial, bottle of tablets or capsules, orbottle of pints or gallons.

The pharmaceutical compositions provided herein may be administered atonce, or multiple times at intervals of time. It is understood that theprecise dosage and duration of treatment may vary with the age, weight,and condition of the patient being treated, and may be determinedempirically using known testing protocols or by extrapolation from invivo or in vitro test or diagnostic data. It is further understood thatfor any particular individual, specific dosage regimens should beadjusted over time according to the individual need and the professionaljudgment of the person administering or supervising the administrationof the formulations.

A. Oral Administration

The pharmaceutical compositions provided herein may be provided insolid, semisolid, or liquid dosage forms for oral administration. Asused herein, oral administration also includes buccal, lingual, andsublingual administration. Suitable oral dosage forms include, but arenot limited to, tablets, capsules, pills, troches, lozenges, pastilles,cachets, pellets, medicated chewing gum, granules, bulk powders,effervescent or non-effervescent powders or granules, solutions,emulsions, suspensions, solutions, wafers, sprinkles, elixirs, andsyrups. In addition to the active ingredient(s), the pharmaceuticalcompositions may contain one or more pharmaceutically acceptablecarriers or excipients, including, but not limited to, binders, fillers,diluents, disintegrants, wetting agents, lubricants, glidants, coloringagents, dye-migration inhibitors, sweetening agents, and flavoringagents.

Binders or granulators impart cohesiveness to a tablet to ensure thetablet remaining intact after compression. Suitable binders orgranulators include, but are not limited to, starches, such as cornstarch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500);gelatin; sugars, such as sucrose, glucose, dextrose, molasses, andlactose; natural and synthetic gums, such as acacia, alginic acid,alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage ofisabgol husks, carboxymethylcellulose, methylcellulose,polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powderedtragacanth, and guar gum; celluloses, such as ethyl cellulose, celluloseacetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxyethylcellulose (HEC),hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC);microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103,AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixturesthereof. Suitable fillers include, but are not limited to, talc, calciumcarbonate, microcrystalline cellulose, powdered cellulose, dextrates,kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinizedstarch, and mixtures thereof. The binder or filler may be present fromabout 50 to about 99% by weight in the pharmaceutical compositionsprovided herein.

Suitable diluents include, but are not limited to, dicalcium phosphate,calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose,kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.Certain diluents, such as mannitol, lactose, sorbitol, sucrose, andinositol, when present in sufficient quantity, can impart properties tosome compressed tablets that permit disintegration in the mouth bychewing. Such compressed tablets can be used as chewable tablets.

Suitable disintegrants include, but are not limited to, agar; bentonite;celluloses, such as methylcellulose and carboxymethylcellulose; woodproducts; natural sponge; cation-exchange resins; alginic acid; gums,such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses,such as croscarmellose; cross-linked polymers, such as crospovidone;cross-linked starches; calcium carbonate; microcrystalline cellulose,such as sodium starch glycolate; polacrilin potassium; starches, such ascorn starch, potato starch, tapioca starch, and pre-gelatinized starch;clays; aligns; and mixtures thereof. The amount of a disintegrant in thepharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The pharmaceutical compositions provided herein may containfrom about 0.5 to about 15% or from about 1 to about 5% by weight of adi sintegrant.

Suitable lubricants include, but are not limited to, calcium stearate;magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol;mannitol; glycols, such as glycerol behenate and polyethylene glycol(PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetableoil, including peanut oil, cottonseed oil, sunflower oil, sesame oil,olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyllaureate; agar; starch; lycopodium; silica or silica gels, such asAEROSIL® 200 (W.R. Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co.of Boston, Mass.); and mixtures thereof. The pharmaceutical compositionsprovided herein may contain about 0.1 to about 5% by weight of alubricant.

Suitable glidants include colloidal silicon dioxide, CAB-O-SIL® (CabotCo. of Boston, Mass.), and asbestos-free talc. Coloring agents includeany of the approved, certified, water soluble FD&C dyes, and waterinsoluble FD&C dyes suspended on alumina hydrate, and color lakes andmixtures thereof. A color lake is the combination by adsorption of awater-soluble dye to a hydrous oxide of a heavy metal, resulting in aninsoluble form of the dye. Flavoring agents include natural flavorsextracted from plants, such as fruits, and synthetic blends of compoundswhich produce a pleasant taste sensation, such as peppermint and methylsalicylate. Sweetening agents include sucrose, lactose, mannitol,syrups, glycerin, and artificial sweeteners, such as saccharin andaspartame. Suitable emulsifying agents include gelatin, acacia,tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitanmonooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN®80), and triethanolamine oleate. Suspending and dispersing agentsinclude sodium carboxymethylcellulose, pectin, tragacanth, Veegum,acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, andpolyvinylpyrrolidone. Preservatives include glycerin, methyl andpropylparaben, benzoic add, sodium benzoate and alcohol. Wetting agentsinclude propylene glycol monostearate, sorbitan monooleate, diethyleneglycol monolaurate, and polyoxyethylene lauryl ether. Solvents includeglycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueousliquids utilized in emulsions include mineral oil and cottonseed oil.Organic acids include citric and tartaric acid. Sources of carbondioxide include sodium bicarbonate and sodium carbonate.

It should be understood that many carriers and excipients may serveseveral functions, even within the same formulation.

The pharmaceutical compositions provided herein may be provided ascompressed tablets, tablet triturates, chewable lozenges, rapidlydissolving tablets, multiple compressed tablets, or enteric-coatingtablets, sugar-coated, or film-coated tablets. Enteric-coated tabletsare compressed tablets coated with substances that resist the action ofstomach acid but dissolve or disintegrate in the intestine, thusprotecting the active ingredients from the acidic environment of thestomach. Enteric-coatings include, but are not limited to, fatty acids,fats, phenyl salicylate, waxes, shellac, ammoniated shellac, andcellulose acetate phthalates. Sugar-coated tablets are compressedtablets surrounded by a sugar coating, which may be beneficial incovering up objectionable tastes or odors and in protecting the tabletsfrom oxidation. Film-coated tablets are compressed tablets that arecovered with a thin layer or film of a water-soluble material. Filmcoatings include, but are not limited to, hydroxyethylcellulose, sodiumcarboxymethylcellulose, polyethylene glycol 4000, and cellulose acetatephthalate. Film coating imparts the same general characteristics assugar coating. Multiple compressed tablets are compressed tablets madeby more than one compression cycle, including layered tablets, andpress-coated or dry-coated tablets.

The tablet dosage forms may be prepared from the active ingredient inpowdered, crystalline, or granular forms, alone or in combination withone or more carriers or excipients described herein, including binders,disintegrants, controlled-release polymers, lubricants, diluents, and/orcolorants. Flavoring and sweetening agents are especially useful in theformation of chewable tablets and lozenges.

The pharmaceutical compositions provided herein may be provided as softor hard capsules, which can be made from gelatin, methylcellulose,starch, or calcium alginate. The hard gelatin capsule, also known as thedry-filled capsule (DFC), consists of two sections, one slipping overthe other, thus completely enclosing the active ingredient. The softelastic capsule (SEC) is a soft, globular shell, such as a gelatinshell, which is plasticized by the addition of glycerin, sorbitol, or asimilar polyol. The soft gelatin shells may contain a preservative toprevent the growth of microorganisms. Suitable preservatives are thoseas described herein, including methyl- and propyl-parabens, and sorbicacid. The liquid, semisolid, and solid dosage forms provided herein maybe encapsulated in a capsule. Suitable liquid and semisolid dosage formsinclude solutions and suspensions in propylene carbonate, vegetableoils, or triglycerides. Capsules containing such solutions can beprepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and4,410,545. The capsules may also be coated as known by those of skill inthe art in order to modify or sustain dissolution of the activeingredient.

The pharmaceutical compositions provided herein may be provided inliquid and semisolid dosage forms, including emulsions, solutions,suspensions, elixirs, and syrups. An emulsion is a two-phase system, inwhich one liquid is dispersed in the form of small globules throughoutanother liquid, which can be oil-in-water or water-in-oil. Emulsions mayinclude a pharmaceutically acceptable non-aqueous liquid or solvent,emulsifying agent, and preservative. Suspensions may include apharmaceutically acceptable suspending agent and preservative. Aqueousalcoholic solutions may include a pharmaceutically acceptable acetal,such as a di(lower alkyl) acetal of a lower alkyl aldehyde, e.g.,acetaldehyde diethyl acetal; and a water-miscible solvent having one ormore hydroxyl groups, such as propylene glycol and ethanol. Elixirs areclear, sweetened, and hydroalcoholic solutions. Syrups are concentratedaqueous solutions of a sugar, for example, sucrose, and may also containa preservative. For a liquid dosage form, for example, a solution in apolyethylene glycol may be diluted with a sufficient quantity of apharmaceutically acceptable liquid carrier, e.g., water, to be measuredconveniently for administration.

Other useful liquid and semisolid dosage forms include, but are notlimited to, those containing the active ingredient(s) provided herein,and a dialkylated mono- or poly-alkylene glycol, including,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 referto the approximate average molecular weight of the polyethylene glycol.These formulations may further comprise one or more antioxidants, suchas butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA),propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, bisulfite, sodium metabisulfite, thiodipropionic acid and itsesters, and dithiocarbamates.

The pharmaceutical compositions provided herein for oral administrationmay be also provided in the forms of liposomes, micelles, microspheres,or nanosystems. Micellar dosage forms can be prepared as described inU.S. Pat. No. 6,350,458.

The pharmaceutical compositions provided herein may be provided asnon-effervescent or effervescent, granules and powders, to bereconstituted into a liquid dosage form. Pharmaceutically acceptablecarriers and excipients used in the non-effervescent granules or powdersmay include diluents, sweeteners, and wetting agents. Pharmaceuticallyacceptable carriers and excipients used in the effervescent granules orpowders may include organic acids and a source of carbon dioxide.

Coloring and flavoring agents can be used in all of the above dosageforms.

The pharmaceutical compositions provided herein may be formulated asimmediate or modified release dosage forms, including delayed-,sustained, pulsed-, controlled, targeted-, and programmed-release forms.

The pharmaceutical compositions provided herein may be co-formulatedwith other active ingredients which do not impair the desiredtherapeutic action, or with substances that supplement the desiredaction.

B. Parenteral Administration

The pharmaceutical compositions provided herein may be administeredparenterally by injection, infusion, or implantation, for local orsystemic administration. Parenteral administration, as used herein,include intravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral, intrasternal, intracranial,intramuscular, intrasynovial, intravesical, and subcutaneousadministration.

The pharmaceutical compositions provided herein may be formulated in anydosage forms that are suitable for parenteral administration, includingsolutions, suspensions, emulsions, micelles, liposomes, microspheres,nanosystems, and solid forms suitable for solutions or suspensions inliquid prior to injection. Such dosage forms can be prepared accordingto conventional methods known to those skilled in the art ofpharmaceutical science (see, Remington: The Science and Practice ofPharmacy, supra).

The pharmaceutical compositions intended for parenteral administrationmay include one or more pharmaceutically acceptable carriers andexcipients, including, but not limited to, aqueous vehicles,water-miscible vehicles, non-aqueous vehicles, antimicrobial agents orpreservatives against the growth of microorganisms, stabilizers,solubility enhancers, isotonic agents, buffering agents, antioxidants,local anesthetics, suspending and dispersing agents, wetting oremulsifying agents, complexing agents, sequestering or chelating agents,cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents,and inert gases.

Suitable aqueous vehicles include, but are not limited to, water,saline, physiological saline or phosphate buffered saline (PBS), sodiumchloride injection, Ringers injection, isotonic dextrose injection,sterile water injection, dextrose and lactated Ringers injection.Non-aqueous vehicles include, but are not limited to, fixed oils ofvegetable origin, castor oil, corn oil, cottonseed oil, olive oil,peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil,hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chaintriglycerides of coconut oil, and palm seed oil. Water-miscible vehiclesinclude, but are not limited to, ethanol, 1,3-butanediol, liquidpolyethylene glycol (e.g., polyethylene glycol 300 and polyethyleneglycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone,N,N-dimethylacetamide, and dimethyl sulfoxide.

Suitable antimicrobial agents or preservatives include, but are notlimited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol,methyl and propyl p-hydroxybenzoates, thimerosal, benzalkonium chloride(e.g., benzethonium chloride), methyl- and propyl-parabens, and sorbicacid. Suitable isotonic agents include, but are not limited to, sodiumchloride, glycerin, and dextrose. Suitable buffering agents include, butare not limited to, phosphate and citrate. Suitable antioxidants arethose as described herein, including bisulfite and sodium metabisulfite.Suitable local anesthetics include, but are not limited to, procainehydrochloride. Suitable suspending and dispersing agents are those asdescribed herein, including sodium carboxymethylcelluose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agentsinclude those described herein, including polyoxyethylene sorbitanmonolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamineoleate. Suitable sequestering or chelating agents include, but are notlimited to EDTA. Suitable pH adjusting agents include, but are notlimited to, sodium hydroxide, hydrochloric acid, citric acid, and lacticacid. Suitable complexing agents include, but are not limited to,cyclodextrins, including α-cyclodextrin, β-cyclodextrin,hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, andsulfobutylether 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

The pharmaceutical compositions provided herein may be formulated forsingle or multiple dosage administration. The single dosage formulationsare packaged in an ampoule, a vial, or a syringe. The multiple dosageparenteral formulations must contain an antimicrobial agent atbacteriostatic or fungistatic concentrations. All parenteralformulations must be sterile, as known and practiced in the art.

In one embodiment, the pharmaceutical compositions are provided asready-to-use sterile solutions. In another embodiment, thepharmaceutical compositions are provided as sterile dry solubleproducts, including lyophilized powders and hypodermic tablets, to bereconstituted with a vehicle prior to use. In yet another embodiment,the pharmaceutical compositions are provided as ready-to-use sterilesuspensions. In yet another embodiment, the pharmaceutical compositionsare provided as sterile dry insoluble products to be reconstituted witha vehicle prior to use. In still another embodiment, the pharmaceuticalcompositions are provided as ready-to-use sterile emulsions.

The pharmaceutical compositions provided herein may be formulated asimmediate or modified release dosage forms, including delayed-,sustained, pulsed-, controlled, targeted-, and programmed-release forms.

The pharmaceutical compositions may be formulated as a suspension,solid, semisolid, or thixotropic liquid, for administration as animplanted depot. In one embodiment, the pharmaceutical compositionsprovided herein are dispersed in a solid inner matrix, which issurrounded by an outer polymeric membrane that is insoluble in bodyfluids but allows the active ingredient in the pharmaceuticalcompositions to diffuse through.

Suitable inner matrixes include polymethylmethacrylate,polybutyl-methacrylate, plasticized or unplasticized polyvinylchloride,plasticized nylon, plasticized polyethylene terephthalate, naturalrubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene,ethylene-vinyl acetate copolymers, silicone rubbers,polydimethylsiloxanes, silicone carbonate copolymers, hydrophilicpolymers, such as hydrogels of esters of acrylic and methacrylic acid,collagen, cross-linked polyvinyl alcohol, and cross-linked partiallyhydrolyzed polyvinyl acetate.

Suitable outer polymeric membranes include polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinyl chloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer.

C. Topical Administration

The pharmaceutical compositions provided herein may be administeredtopically to the skin, orifices, or mucosa. The topical administration,as used herein, includes (intra)dermal, conjunctival, intracorneal,intraocular, ophthalmic, auricular, transdermal, nasal, vaginal,urethral, respiratory, and rectal administration.

The pharmaceutical compositions provided herein may be formulated in anydosage forms that are suitable for topical administration for local orsystemic effect, including emulsions, solutions, suspensions, creams,gels, hydrogels, ointments, dusting powders, dressings, elixirs,lotions, suspensions, tinctures, pastes, foams, films, aerosols,irrigations, sprays, suppositories, bandages, dermal patches. Thetopical formulation of the pharmaceutical compositions provided hereinmay also comprise liposomes, micelles, microspheres, nanosystems, andmixtures thereof.

Pharmaceutically acceptable carriers and excipients suitable for use inthe topical formulations provided herein include, but are not limitedto, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles,antimicrobial agents or preservatives against the growth ofmicroorganisms, stabilizers, solubility enhancers, isotonic agents,buffering agents, antioxidants, local anesthetics, suspending anddispersing agents, wetting or emulsifying agents, complexing agents,sequestering or chelating agents, penetration enhancers,cryoprotectants, lyoprotectants, thickening agents, and inert gases.

The pharmaceutical compositions may also be administered topically byelectroporation, iontophoresis, phonophoresis, sonophoresis, ormicroneedle or needle-free injection, such as POWDERJECT™ (Chiron Corp.,Emeryville, Calif.), and BIOJECT™ (Bioject Medical Technologies Inc.,Tualatin, Oreg.).

The pharmaceutical compositions provided herein may be provided in theforms of ointments, creams, and gels. Suitable ointment vehicles includeoleaginous or hydrocarbon vehicles, including lard, benzoinated lard,olive oil, cottonseed oil, and other oils, white petrolatum;emulsifiable or absorption vehicles, such as hydrophilic petrolatum,hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles,such as hydrophilic ointment; water-soluble ointment vehicles, includingpolyethylene glycols of varying molecular weight; emulsion vehicles,either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions,including cetyl alcohol, glyceryl monostearate, lanolin, and stearicacid (see, Remington: The Science and Practice of Pharmacy, supra).These vehicles are emollient but generally require addition ofantioxidants and preservatives.

Suitable cream base can be oil-in-water or water-in-oil. Cream vehiclesmay be water-washable, and contain an oil phase, an emulsifier, and anaqueous phase. The oil phase is also called the “internal” phase, whichis generally comprised of petrolatum and a fatty alcohol such as cetylor stearyl alcohol. The aqueous phase usually, although not necessarily,exceeds the oil phase in volume, and generally contains a humectant. Theemulsifier in a cream formulation may be a nonionic, anionic, cationic,or amphoteric surfactant.

Gels are semisolid, suspension-type systems. Single-phase gels containorganic macromolecules distributed substantially uniformly throughoutthe liquid carrier. Suitable gelling agents include crosslinked acrylicacid polymers, such as carbomers, carboxypolyalkylenes, CARBOPOL®;hydrophilic polymers, such as polyethylene oxides,polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol;cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulosephthalate, and methylcellulose; gums, such as tragacanth and xanthangum; sodium alginate; and gelatin. In order to prepare a uniform gel,dispersing agents such as alcohol or glycerin can be added, or thegelling agent can be dispersed by trituration, mechanical mixing, and/orstirring.

The pharmaceutical compositions provided herein may be administeredrectally, urethrally, vaginally, or perivaginally in the forms ofsuppositories, pessaries, bougies, poultices or cataplasm, pastes,powders, dressings, creams, plasters, contraceptives, ointments,solutions, emulsions, suspensions, tampons, gels, foams, sprays, orenemas. These dosage forms can be manufactured using conventionalprocesses as described in Remington: The Science and Practice ofPharmacy, supra.

Rectal, urethral, and vaginal suppositories are solid bodies forinsertion into body orifices, which are solid at ordinary temperaturesbut melt or soften at body temperature to release the activeingredient(s) inside the orifices. Pharmaceutically acceptable carriersutilized in rectal and vaginal suppositories include bases or vehicles,such as stiffening agents, which produce a melting point in theproximity of body temperature, when formulated with the pharmaceuticalcompositions provided herein; and antioxidants as described herein,including bisulfite and sodium metabisulfite. Suitable vehicles include,but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin,carbowax (polyoxyethylene glycol), spermaceti, paraffin, white andyellow wax, and appropriate mixtures of mono-, di- and triglycerides offatty acids, hydrogels, such as polyvinyl alcohol, hydroxyethylmethacrylate, polyacrylic acid; glycerinated gelatin. Combinations ofthe various vehicles may be used. Rectal and vaginal suppositories maybe prepared by the compressed method or molding. The typical weight of arectal and vaginal suppository is about 2 to about 3 g.

The pharmaceutical compositions provided herein may be administeredophthalmically in the forms of solutions, suspensions, ointments,emulsions, gel-forming solutions, powders for solutions, gels, ocularinserts, and implants.

The pharmaceutical compositions provided herein may be administeredintranasally or by inhalation to the respiratory tract. Thepharmaceutical compositions may be provided in the form of an aerosol orsolution for delivery using a pressurized container, pump, spray,atomizer, such as an atomizer using electrohydrodynamics to produce afine mist, or nebulizer, alone or in combination with a suitablepropellant, such as 1,1,1,2-tetrafluoroethane or1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions mayalso be provided as a dry powder for insufflation, alone or incombination with an inert carrier such as lactose or phospholipids; andnasal drops. For intranasal use, the powder may comprise a bioadhesiveagent, including chitosan or cyclodextrin.

Solutions or suspensions for use in a pressurized container, pump,spray, atomizer, or nebulizer may be formulated to contain ethanol,aqueous ethanol, or a suitable alternative agent for dispersing,solubilizing, or extending release of the active ingredient providedherein, a propellant as solvent; and/or a surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

The pharmaceutical compositions provided herein may be micronized to asize suitable for delivery by inhalation, such as about 50 micrometersor less, or about 10 micrometers or less. Particles of such sizes may beprepared using a comminuting method known to those skilled in the art,such as spiral jet milling, fluid bed jet milling, supercritical fluidprocessing to form nanoparticles, high pressure homogenization, or spraydrying.

Capsules, blisters and cartridges for use in an inhaler or insufflatormay be formulated to contain a powder mix of the pharmaceuticalcompositions provided herein; a suitable powder base, such as lactose orstarch; and a performance modifier, such as l-leucine, mannitol, ormagnesium stearate. The lactose may be anhydrous or in the form of themonohydrate. Other suitable excipients or carriers include dextran,glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.The pharmaceutical compositions provided herein for inhaled/intranasaladministration may further comprise a suitable flavor, such as mentholand levomenthol, or sweeteners, such as saccharin or saccharin sodium.

The pharmaceutical compositions provided herein for topicaladministration may be formulated to be immediate release or modifiedrelease, including delayed-, sustained-, pulsed-, controlled-, targeted,and programmed release.

D. Modified Release

The pharmaceutical compositions provided herein may be formulated as amodified release dosage form. As used herein, the term “modifiedrelease” refers to a dosage form in which the rate or place of releaseof the active ingredient(s) is different from that of an immediatedosage form when administered by the same route. Modified release dosageforms include delayed-, extended-, prolonged-, sustained-, pulsatile-,controlled-, accelerated- and fast-, targeted-, programmed-release, andgastric retention dosage forms. The pharmaceutical compositions inmodified release dosage forms can be prepared using a variety ofmodified release devices and methods known to those skilled in the art,including, but not limited to, matrix controlled release devices,osmotic controlled release devices, multiparticulate controlled releasedevices, ion-exchange resins, enteric coatings, multilayered coatings,microspheres, liposomes, and combinations thereof. The release rate ofthe active ingredient(s) can also be modified by varying the particlesizes and polymorphorism of the active ingredient(s).

Examples of modified release include, but are not limited to, thosedescribed in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123;4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543;5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474;5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324;6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461;6,419,961; 6,589,548; 6,613,358; and 6,699,500.

1. Matrix Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form may be fabricated using a matrix controlled release deviceknown to those skilled in the art (see, Takada et al in “Encyclopedia ofControlled Drug Delivery,” Vol. 2, Mathiowitz Ed., Wiley, 1999).

In one embodiment, the pharmaceutical compositions provided herein in amodified release dosage form is formulated using an erodible matrixdevice, which is water-swellable, erodible, or soluble polymers,including synthetic polymers, and naturally occurring polymers andderivatives, such as polysaccharides and proteins.

Materials useful in forming an erodible matrix include, but are notlimited to, chitin, chitosan, dextran, and pullulan; gum agar, gumarabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gumghatti, guar gum, xanthan gum, and scleroglucan; starches, such asdextrin and maltodextrin; hydrophilic colloids, such as pectin;phosphatides, such as lecithin; alginates; propylene glycol alginate;gelatin; collagen; and cellulosics, such as ethyl cellulose (EC),methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), celluloseacetate (CA), cellulose propionate (CP), cellulose butyrate (CB),cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetatetrimellitate (HPMCAT), and ethylhydroxy ethylcellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acidesters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acidor methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, N.J.);poly(2-hydroxyethyl-methacrylate); polylactides; copolymers ofL-glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolicacid copolymers; poly-D-(−)-3-hydroxybutyric acid; and other acrylicacid derivatives, such as homopolymers and copolymers ofbutylmethacrylate, methylmethacrylate, ethylmethacrylate, ethylacrylate,(2-dimethylaminoethyl)methacrylate, and(trimethylaminoethyl)methacrylate chloride.

In further embodiments, the pharmaceutical compositions are formulatedwith a non-erodible matrix device. The active ingredient(s) is dissolvedor dispersed in an inert matrix and is released primarily by diffusionthrough the inert matrix once administered. Materials suitable for useas a non-erodible matrix device included, but are not limited to,insoluble plastics, such as polyethylene, polypropylene, polyisoprene,polyisobutylene, polybutadiene, polymethylmethacrylate,polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride,methyl acrylate-methyl methacrylate copolymers, ethylene-vinyl acetatecopolymers, ethylene/propylene copolymers, ethylene/ethyl acrylatecopolymers, vinyl chloride copolymers with vinyl acetate, vinylidenechloride, ethylene and propylene, ionomer polyethylene terephthalate,butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticizednylon, plasticized polyethylene terephthalate, natural rubber, siliconerubbers, polydimethylsiloxanes, silicone carbonate copolymers, and;hydrophilic polymers, such as ethyl cellulose, cellulose acetate,crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate;and fatty compounds, such as carnauba wax, microcrystalline wax, andtriglycerides.

In a matrix controlled release system, the desired release kinetics canbe controlled, for example, via the polymer type employed, the polymerviscosity, the particle sizes of the polymer and/or the activeingredient(s), the ratio of the active ingredient(s) versus the polymer,and other excipients or carriers in the compositions.

The pharmaceutical compositions provided herein in a modified releasedosage form may be prepared by methods known to those skilled in theart, including direct compression, dry or wet granulation followed bycompression, melt-granulation followed by compression.

2. Osmotic Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form may be fabricated using an osmotic controlled releasedevice, including one-chamber system, two-chamber system, asymmetricmembrane technology (AMT), and extruding core system (ECS). In general,such devices have at least two components: (a) the core which containsthe active ingredient(s); and (b) a semipermeable membrane with at leastone delivery port, which encapsulates the core. The semipermeablemembrane controls the influx of water to the core from an aqueousenvironment of use so as to cause drug release by extrusion through thedelivery port(s).

In addition to the active ingredient(s), the core of the osmotic deviceoptionally includes an osmotic agent, which creates a driving force fortransport of water from the environment of use into the core of thedevice. One class of osmotic agents water-swellable hydrophilicpolymers, which are also referred to as “osmopolymers” and “hydrogels,”including, but not limited to, hydrophilic vinyl and acrylic polymers,polysaccharides such as calcium alginate, polyethylene oxide (PEO),polyethylene glycol (PEG), polypropylene glycol (PPG),poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic)acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol(PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomerssuch as methyl methacrylate and vinyl acetate, hydrophilic polyurethanescontaining large PEO blocks, sodium croscarmellose, carrageenan,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC),hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) andcarboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin,xanthan gum, and sodium starch glycolate.

The other class of osmotic agents is osmogens, which are capable ofimbibing water to affect an osmotic pressure gradient across the barrierof the surrounding coating. Suitable osmogens include, but are notlimited to, inorganic salts, such as magnesium sulfate, magnesiumchloride, calcium chloride, sodium chloride, lithium chloride, potassiumsulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithiumsulfate, potassium chloride, and sodium sulfate; sugars, such asdextrose, fructose, glucose, inositol, lactose, maltose, mannitol,raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids,such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleicacid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamicacid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea;and mixtures thereof.

Osmotic agents of different dissolution rates may be employed toinfluence how rapidly the active ingredient(s) is initially deliveredfrom the dosage form. For example, amorphous sugars, such as MANNOGEM™EZ (SPI Pharma, Lewes, Del.) can be used to provide faster deliveryduring the first couple of hours to promptly produce the desiredtherapeutic effect, and gradually and continually release of theremaining amount to maintain the desired level of therapeutic orprophylactic effect over an extended period of time. In this case, theactive ingredient(s) is released at such a rate to replace the amount ofthe active ingredient metabolized and excreted.

The core may also include a wide variety of other excipients andcarriers as described herein to enhance the performance of the dosageform or to promote stability or processing.

Materials useful in forming the semipermeable membrane include variousgrades of acrylics, vinyls, ethers, polyamides, polyesters, andcellulosic derivatives that are water-permeable and water-insoluble atphysiologically relevant pHs, or are susceptible to being renderedwater-insoluble by chemical alteration, such as crosslinking. Examplesof suitable polymers useful in forming the coating, include plasticized,unplasticized, and reinforced cellulose acetate (CA), cellulosediacetate, cellulose triacetate, CA propionate, cellulose nitrate,cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methylcarbamate, CA succinate, cellulose acetate trimellitate (CAT), CAdimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyloxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, beta glucan acetate, betaglucan triacetate, acetaldehyde dimethyl acetate, triacetate of locustbean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPGcopolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT,poly(acrylic) acids and esters and poly-(methacrylic) acids and estersand copolymers thereof, starch, dextran, dextrin, chitosan, collagen,gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones,polystyrenes, polyvinyl halides, polyvinyl esters and ethers, naturalwaxes, and synthetic waxes.

Semipermeable membrane may also be a hydrophobic microporous membrane,wherein the pores are substantially filled with a gas and are not wettedby the aqueous medium but are permeable to water vapor, as disclosed inU.S. Pat. No. 5,798,119. Such hydrophobic but water-vapor permeablemembrane are typically composed of hydrophobic polymers such aspolyalkenes, polyethylene, polypropylene, polytetrafluoroethylene,polyacrylic acid derivatives, polyethers, polysulfones,polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidenefluoride, polyvinyl esters and ethers, natural waxes, and syntheticwaxes.

The delivery port(s) on the semipermeable membrane may be formedpost-coating by mechanical or laser drilling. Delivery port(s) may alsobe formed in situ by erosion of a plug of water-soluble material or byrupture of a thinner portion of the membrane over an indentation in thecore. In addition, delivery ports may be formed during coating process,as in the case of asymmetric membrane coatings of the type disclosed inU.S. Pat. Nos. 5,612,059 and 5,698,220.

The total amount of the active ingredient(s) released and the releaserate can substantially by modulated via the thickness and porosity ofthe semipermeable membrane, the composition of the core, and the number,size, and position of the delivery ports.

The pharmaceutical compositions in an osmotic controlled-release dosageform may further comprise additional conventional excipients or carriersas described herein to promote performance or processing of theformulation.

The osmotic controlled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art(see, Remington: The Science and Practice of Pharmacy, supra; Santus andBaker, J. Controlled Release 1995, 35, 1-21; Verma et al., DrugDevelopment and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J.Controlled Release 2002, 79, 7-27).

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as AMT controlled-release dosage form, which comprises anasymmetric osmotic membrane that coats a core comprising the activeingredient(s) and other pharmaceutically acceptable excipients orcarriers. See, U.S. Pat. No. 5,612,059 and WO 2002/17918. The AMTcontrolled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art,including direct compression, dry granulation, wet granulation, and adip-coating method.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as ESC controlled-release dosage form, which comprises anosmotic membrane that coats a core comprising the active ingredient(s),a hydroxylethyl cellulose, and other pharmaceutically acceptableexcipients or carriers.

3. Multiparticulate Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form may be fabricated as a multiparticulate controlled releasedevice, which comprises a multiplicity of particles, granules, orpellets, ranging from about 10 μm to about 3 mm, about 50 μm to about2.5 mm, or from about 100 μm to about 1 mm in diameter. Suchmultiparticulates may be made by the processes known to those skilled inthe art, including wet- and dry-granulation, extrusion/spheronization,roller-compaction, melt-congealing, and by spray-coating seed cores.See, for example, Multiparticulate Oral Drug Delivery; Marcel Dekker:1994; and Pharmaceutical Pelletization Technology; Marcel Dekker: 1989.

Other excipients or carriers as described herein may be blended with thepharmaceutical compositions to aid in processing and forming themultiparticulates. The resulting particles may themselves constitute themultiparticulate device or may be coated by various film-formingmaterials, such as enteric polymers, water-swellable, and water-solublepolymers. The multiparticulates can be further processed as a capsule ora tablet.

4. Targeted Delivery

The pharmaceutical compositions provided herein may also be formulatedto be targeted to a particular tissue, receptor, or other area of thebody of the subject to be treated, including liposome-, resealederythrocyte-, and antibody-based delivery systems. Examples include, butare not limited to, U.S. Pat. Nos. 6,316,652; 6,274,552; 6,271,359;6,253,872; 6,139,865; 6,131,570; 6,120,751; 6,071,495; 6,060,082;6,048,736; 6,039,975; 6,004,534; 5,985,307; 5,972,366; 5,900,252;5,840,674; 5,759,542; and 5,709,874.

Methods of Use

In one embodiment, provided herein are methods for treating a cyanidepoisoning, which comprises administering to a subject a therapeuticallyeffective amount of sodium nitrite provided herein. In one embodiment,the subject is a mammal. In another embodiment, the subject is a human.In certain embodiments, the method further comprises the administrationto the subject a therapeutically effective amount of sodium thiosulfate(e.g., sodium thiosulfate pentahydrate). In certain embodiments, themethod further comprises the administration to the subject atherapeutically effective amount of pharmaceutical grade sodiumthiosulfate (e.g., pharmaceutical grade sodium thiosulfatepentahydrate). Suitable forms of and methods for makingpharmaceutical-grade sodium thiosulfate for co-administration withsodium nitrite are provided in U.S. Provisional Application No.61/223,993, filed on Jul. 8, 2009, titled SODIUM THIOSULFATE-CONTAININGPHARMACEUTICAL COMPOSITIONS, which is incorporated by reference hereinin its entirety, as well as in Example 6 set forth herein. In certainembodiments, pharmaceutical grade sodium thiosulfate is characterized byone or more of the following:

containing no less than about 99% by weight and/or no greater than about100.5% by weight of sodium thiosulfate on an anhydrous basis;

having a pH between about 6 to about 8 when measured in a 10% solutionat 25° C.;

having water content of about 32% to about 37% by weight;

having an appearance of colorless crystals;

having a clear and colorless appearance as a 10% solution;

having no odor;

having a positive identification test for sodium;

having a positive identification test for thiosulfate;

having no turbidy when mixed with ammonium oxalate TS;

having heavy metal content of no greater than about 10 ppm;

containing no greater than about 0.01% by weight of carbonate;

containing no greater than about 0.005% by weight of insoluble matter;

containing no greater than about 200 ppm of chloride;

containing no greater than about 0.001% by weight of sulfide; containingno greater than about 0.05% or no greater than about 0.1% by weight ofsulfite;

containing no greater than about 0.05%, no greater than about 0.1%, nogreater than about 0.25%, or no greater than about 0.5% by weight ofsulfate;

containing no greater than about 0.002% by weight of iron;

containing no greater than about 0.01% by weight of calcium;

containing no greater than about 0.005% by weight of potassium;

containing no greater than about 10 ppm, no greater than about 100 ppm,no greater than about 500 ppm, no greater than about 1000 ppm, or nogreater than 5000 ppm of organic volatile impurities;

having total NVOC or NPOC of no greater than 60 ppb, no greater thanabout 2.5 ppm, no greater than about 8 ppm, no greater than about 10ppm, no greater than about 20 ppm, no greater than about 25 ppm, or nogreater than about 50 ppm;

containing no greater than about 0.05 ppm of mercury;

containing no greater than about 2 ppm of aluminum;

containing no greater than about 3 ppm of arsenic;

containing no greater than 0.001% by weight of lead;

containing no greater than about 0.002% by weight of nitrogen compounds(as N);

containing no greater than about 0.003% by weight of selenium;

having a total aerobic count of microbial load of no greater than about100 CFU/g;

having a total yeast and mold count of no greater than about 20 CFU/g;and

containing no greater than about 0.02 EU/mg, no greater than about 0.1EU/mg, or no greater than about 0.25 EU/mg of bacterial endotoxins.

In certain embodiments, the sodium nitrite administered to the subjectis not acidified.

In another embodiment, provided herein are methods for treating ahydrogen sulfide poisoning, which comprises administering to a subject atherapeutically effective amount of sodium nitrite provided herein. Inone embodiment, the subject is a mammal. In another embodiment, thesubject is a human. In certain embodiments, the sodium nitriteadministered to the subject is not acidified.

In yet another embodiment, provided herein is a method for treating acardiovascular disease or a condition associated with the cardiovascularsystem, including, but not limited to, high blood pressure, pulmonaryhypertension, cerebral vasospasm, angina, claudication, peripheralartery disease, critical limb ischemia and tissue ischemia-reperfusioninjury, which comprises administering to a subject a therapeuticallyeffective amount of sodium nitrite provided herein. In one embodiment,the subject is a mammal. In another embodiment, the subject is a human.In certain embodiments, the sodium nitrite administered to the subjectis not acidified.

In certain embodiments, the condition associated with the cardiovascularsystem is one or more of pulmonary hypertension (e.g., neonatalpulmonary hypertension, primary pulmonary hypertension, and secondarypulmonary hypertension), systemic hypertension, cutaneous ulceration,acute renal failure, chronic renal failure, intravascular thrombosis,and an ischemic central nervous system event.

In yet another embodiment, provided herein is a method for treating acondition associated with elevated blood pressure, which comprisesadministering to a subject a therapeutically effective amount of sodiumnitrite provided herein. In one embodiment, the subject is a mammal. Inanother embodiment, the subject is a human. In certain embodiments, thesodium nitrite administered to the subject is not acidified.

In yet another embodiment, provided herein is a method for increasingblood flow to tissues, for example, to tissues in regions of low oxygentension, which comprises administering to a subject a therapeuticallyeffective amount of sodium nitrite provided herein. In one embodiment,the subject is a mammal. In another embodiment, the subject is a human.In certain embodiments, the sodium nitrite administered to the subjectis not acidified.

In yet another embodiment, provided herein is a method for stimulatingthe growth of new blood vessels, for example, within tissues in regionsof poor circulation and low oxygen tension, which comprisesadministering to a subject a therapeutically effective amount of sodiumnitrite provided herein. In one embodiment, the subject is a mammal. Inanother embodiment, the subject is a human. In certain embodiments, thesodium nitrite administered to the subject is not acidified.

In certain embodiments, the decreased blood flow to the tissue is causeddirectly or indirectly by at least one of the following conditions:sickle cell anemia, thalassemia, hemoglobin C disease, hemoglobin SCdisease, sickle thalassemia, hereditary spherocytosis, hereditaryelliptocytosis, hereditary ovalcytosis, glucose-6-phosphate deficiencyand other red blood cell enzyme deficiencies, paroxysmal nocturnalhemoglobinuria (PNH), paroxysmal cold hemoglobinuria (PCH), thromboticthrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), idiopathicautoimmune hemolytic anemia, drug-induced immune hemolytic anemia,secondary immune hemolytic anemia, non-immune hemolytic anemia caused bychemical or physical agents, malaria, falciparum malaria, bartonellosis,babesiosis, clostridial infection, severe Haemophilus influenzae type binfection, extensive burns, transfusion reaction, rhabdomyolysis(myoglobinemia), transfusion of aged blood, transfusion of hemoglobin,transfusion of red blood cells, cardiopulmonary bypass, coronarydisease, cardiac ischemia syndrome, angina, iatrogenic hemolysis,angioplasty, myocardial ischemia, tissue ischemia, hemolysis caused byintravascular devices, hemodialysis, pulmonary hypertension, systemichypertension, cutaneous ulceration, acute renal failure, chronic renalfailure, intravascular thrombosis, and an ischemic central nervoussystem event. In certain embodiments, the tissue is an ischemic tissue.

In yet another embodiment, provided herein is a method for treatinghemolytic condition, which comprises administering to a subject atherapeutically effective amount of sodium nitrite provided herein. Inone embodiment, the subject is a mammal. In another embodiment, thesubject is a human. In certain embodiments, the sodium nitriteadministered to the subject is not acidified.

In certain embodiments, the hemolytic condition includes one or more ofsickle cell anemia, thalassemia, hemoglobin C disease, hemoglobin SCdisease, sickle thalassemia, hereditary spherocytosis, hereditaryelliptocytosis, hereditary ovalcytosis, glucose-6-phosphate deficiencyand other red blood cell enzyme deficiencies, paroxysmal nocturnalhemoglobinuria (PNH), paroxysmal cold hemoglobinuria (PCH), thromboticthrombocytopenic purpura/hemolytic uremic syndrome (TTP/HITS),idiopathic autoimmune hemolytic anemia, drug-induced immune hemolyticanemia, secondary immune hemolytic anemia, non-immune hemolytic anemiacaused by chemical or physical agents, malaria, falciparum malaria,bartonellosis, babesiosis, clostridial infection, severe Haemophilusinfluenzae type b infection, extensive burns, transfusion reaction,rhabdomyolysis (myoglobinemia}, transfusion of aged blood,cardiopulomonary bypass, and hemodialysis.

In yet another embodiment, provided herein are methods for treating arespiratory disease or a condition associated with the tracheo-pulmonarysystem, including, but not limited to, cystic fibrosis, pulmonarytuberculosis, mycotic pneumonia, bacterial pneumonia, viral pneumonia,pulmonary abscess, pulmonary hypertension, pulmonary embolism, andpulmonary vasospasm, which comprises administering to a subject atherapeutically effective amount of sodium nitrite provided herein.

In yet another embodiment, provided herein are methods for treating adermatological disease or a condition associated with the skin,including, but not limited to, bacterial infection of the skin, mycoticinfection of the skin, viral infection of the skin, mycotic infection ofthe nails, bacterial infection of the nails, viral infection of thenails, mycotic infection of the nailbeds, bacterial infection of thenailbeds, viral infection of the nailbeds, psoriasis, scleroderma,inflammation of the skin, inflammation of the nails, and inflammation ofthe nailbeds, which comprises administering to a subject atherapeutically effective amount of sodium nitrite provided herein.

In still another embodiment, provided herein are methods for treating,preventing or reducing the risk of hospital-acquired infections, such asnocosomial infections, which can originate from the insertion of adevice (e.g., a medical device) and/or the use of a device in the body.In one embodiment, the infection is caused by or associated with S.aureus. Such uses and devices are set forth in U.S. Patent ApplicationPublication No. 2007/0239107, the disclosure of which is incorporatedherein by reference in its entirety. Examples of such devices include,but are not limited to, urinary catheters, intratracheal tubes, vascularcatheters, vascular catheter ports, wound drain tubes, gastric tubes. Incertain embodiments, the sodium nitrite administered to the subject isacidified or administered in combination with an acidifying agent (e.g.,and acid).

In certain embodiments, provided herein are methods for the preparationor manufacture of a medicament for the treatment, prevention ormanagement of a disease or disorder provided herein, or a symptomthereof.

Depending on the condition, disorder, or disease, to be treated and thesubject's condition, the sodium nitrite provided herein may beadministered by oral, parenteral (e.g., intramuscular, intraperitoneal,intravenous, ICV, intracistemal injection or infusion, subcutaneousinjection, or implant), inhalation, nasal, vaginal, rectal, sublingual,or topical (e.g., transdermal or local) routes of administration, andmay be formulated, alone or together, in suitable dosage unit withpharmaceutically acceptable carriers, adjuvants and vehicles appropriatefor each route of administration.

The dose may be in the form of one, two, three, four, five, six, or moresub-doses that are administered at appropriate intervals per day. Thedose or sub-doses can be administered in the form of dosage unitscontaining from about 10 ng to about 1000 mg, from about 20 ng to about5 mg, from about 50 ng to about 1 mg, from about 50 ng to about 0.2 mg,or from about 50 ng to about 0.5 mg active ingredient(s) per dosageunit, and if the condition of the patient requires, the dose can, by wayof alternative, be administered as a continuous infusion.

In certain embodiments, an appropriate dosage level is about 0.01 toabout 100 mg per kg patient body weight per day (mg/kg per day), about0.01 to about 50 mg/kg per day, about 0.01 to about 25 mg/kg per day, orabout 0.05 to about 10 mg/kg per day, which may be administered insingle or multiple doses. A suitable dosage level may be about 0.01 toabout 100 mg/kg per day, about 0.05 to about 50 mg/kg per day, or about0.1 to about 10 mg/kg per day. Within this range the dosage may be about0.01 to about 0.1, about 0.1 to about 1.0, about 1.0 to about 10, orabout 10 to about 50 mg/kg per day.

In certain embodiments of the methods provided herein, thetherapeutically effective amount of sodium nitrite administered to thesubject does not induce toxic levels of methemoglobin, and in manyembodiments does not induce formation of clinically significant amountsof methemoglobin in the subject. In certain embodiments, the effectiveamount of sodium nitrite administered to the subject induces productionin the subject of no greater than about 25%, no greater than about 20%,no greater than about 10%, no greater than about 8%, no greater thanabout 5%, no greater than about 3%, no greater than about 2%, no greaterthan about 1% methemoglobin.

In certain embodiments of the methods provided herein, thetherapeutically effective amount of sodium nitrite is administered oneor more times per day, per week, per month, per year or longer. Incertain embodiments of the methods provided herein, the therapeuticallyeffective amount of sodium nitrite is administered intermittently orchronically. In certain embodiments of the methods provided herein, thetherapeutically effective amount of sodium nitrite is administeredintermittently or continuously for one or more hours, days, weeks,months, years or longer.

Combination Therapy

The sodium nitrite provided herein may also be combined or used incombination with other therapeutic agents useful in the treatment and/orprevention of the diseases and conditions provided herein.

As used herein, the term “in combination” includes the use of more thanone therapy (e.g., one or more prophylactic and/or therapeutic agents).However, the use of the term “in combination” does not restrict theorder in which therapies (e.g., prophylactic and/or therapeutic agents)are administered to a subject with a disease or disorder. A firsttherapy (e.g., a prophylactic or therapeutic agent such as a compoundprovided herein) can be administered prior to (e.g., 5 minutes, 15minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks,4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantlywith, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6weeks, 8 weeks, or 12 weeks after) the administration of a secondtherapy (e.g., a prophylactic or therapeutic agent) to the subject.Triple therapy is also contemplated herein.

As used herein, the term “synergistic” includes a combination of thesodium nitrite provided herein and another therapy (e.g., a prophylacticor therapeutic agent) which has been or is currently being used totreat, prevent, or manage a disease or disorder, which is more effectivethan the additive effects of the therapies. A synergistic effect of acombination of therapies (e.g., a combination of prophylactic ortherapeutic agents) permits the use of lower dosages of one or more ofthe therapies and/or less frequent administration of said therapies to asubject with a disorder. The ability to utilize lower dosages of atherapy (e.g., a prophylactic or therapeutic agent) and/or to administersaid therapy less frequently reduces the toxicity associated with theadministration of said therapy to a subject without reducing theefficacy of said therapy in the prevention or treatment of a disorder).In addition, a synergistic effect can result in improved efficacy ofagents in the prevention or treatment of a disorder. Finally, asynergistic effect of a combination of therapies (e.g., a combination ofprophylactic or therapeutic agents) may avoid or reduce adverse orunwanted side effects associated with the use of either therapy alone.

The sodium nitrite provided herein can be administered in combination oralternation with another therapeutic agent. In combination therapy,effective dosages of two or more agents are administered together,whereas in alternation or sequential-step therapy, an effective dosageof each agent is administered serially or sequentially. The dosagesgiven will depend on absorption, inactivation and excretion rates of thedrug as well as other factors known to those of skill in the art. It isto be noted that dosage values will also vary with the severity of thecondition to be alleviated. It is to be further understood that for anyparticular subject, specific dosage regimens and schedules should beadjusted over time according to the individual need and the professionaljudgment of the person administering or supervising the administrationof the compositions.

The compounds provided herein can be administered in combination withother classes of compounds, including, but not limited to, endothelinconverting enzyme (ECE) inhibitors, such as phosphoramidon; thromboxanereceptor antagonists, such as ifetroban; potassium channel openers;thrombin inhibitors, such as hirudin; growth factor inhibitors, such asmodulators of PDGF activity; platelet activating factor (PAF)antagonists; anti-platelet agents, such as GPIIb/IIIa blockers (e.g.,abciximab, eptifibatide, and tirofiban), P2Y(AC) antagonists (e.g.,clopidogrel, ticlopidine and CS-747), and aspirin; anticoagulants, suchas warfarin; low molecular weight heparins, such as enoxaparin; FactorVIIa Inhibitors and Factor Xa Inhibitors; renin inhibitors; neutralendopeptidase (NEP) inhibitors; vasopeptidase inhibitors (dual NEP-ACEinhibitors), such as omapatrilat and gemopatrilat; HMG CoA reductaseinhibitors, such as pravastatin, lovastatin, atorvastatin, simvastatin,NK-104 (a.k.a. itavastatin, nisvastatin, or nisbastatin), and ZD-4522(also known as rosuvastatin, atavastatin, or visastatin); squalenesynthetase inhibitors; fibrates; bile acid sequestrants, such asquestran; niacin; anti-atherosclerotic agents, such as ACAT inhibitors;MTP Inhibitors; calcium channel blockers, such as amlodipine besylate;potassium channel activators; alpha-adrenergic agents; beta-adrenergicagents, such as carvedilol and metoprolol; antiarrhythmic agents;diuretics, such as chlorothiazide, hydrochlorothiazide, flumethiazide,hydroflumethiazide, bendroflumethiazide, methylchlorothiazide,trichloromethiazide, polythiazide, benzothiazide, ethacrynic acid,ticrynafen, chlorthalidone, furosenide, muzolimine, bumetanide,triamterene, amiloride, and spironolactone; thrombolytic agents, such astissue plasminogen activator (tPA), recombinant tPA, streptokinase,urokinase, prourokinase, and anisoylated plasminogen streptokinaseactivator complex (APSAC); anti-diabetic agents, such as biguanides(e.g., metformin), glucosidase inhibitors (e.g., acarbose), insulins,meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride,glyburide, and glipizide), thiozolidinediones (e.g., troglitazone,rosiglitazone, and pioglitazone), and PPAR-gamma agonists;mineralocorticoid receptor antagonists, such as spironolactone andeplerenone; growth hormone secretagogues; aP2 inhibitors;phosphodiesterase inhibitors, such as PDE III inhibitors (e.g.,cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, andvardenafil); protein tyrosine kinase inhibitors; antiinflammatories;antiproliferatives, such as methotrexate, FK506 (tacrolimus),mycophenolate mofetil; chemotherapeutic agents; immunosuppressants;anticancer agents and cytotoxic agents (e.g., alkylating agents, such asnitrogen mustards, alkyl sulfonates, nitrosoureas, ethylenimines, andtriazenes); antimetabolites, such as folate antagonists, purineanalogues, and pyrimidine analogues; antibiotics, such asanthracyclines, bleomycins, mitomycin, dactinomycin, and plicamycin;enzymes, such as L-asparaginase; farnesyl-protein transferaseinhibitors; hormonal agents, such as glucocorticoids (e.g., cortisone),estrogens/antiestrogens, androgens/antiandrogens, progestins, andluteinizing hormone-releasing hormone antagonists, and octreotideacetate; microtubule-disruptor agents, such as ecteinascidins;microtubule-stabilizing agents, such as pacitaxel, docetaxel, andepothilones A-F; plant-derived products, such as vinca alkaloids,epipodophyllotoxins, and taxanes; and topoisomerase inhibitors;prenyl-protein transferase inhibitors; and cyclosporins; steroids, suchas prednisone and dexamethasone; cytotoxic drugs, such as azathioprineand cyclophosphamide; TNF-alpha inhibitors, such as tenidap; anti-TNFantibodies or soluble TNF receptor, such as etanercept, rapamycin, andleflunimide; cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib androfecoxib; and miscellaneous agents such as, sodium thiosulfate,hydroxyurea, procarbazine, mitotane, hexamethylmelamine, gold compounds,platinum coordination complexes, such as cisplatin, satraplatin, andcarboplatin.

The sodium nitrite provided herein can also be provided as an article ofmanufacture using packaging materials well known to those of skill inthe art. See, e.g., U.S. Pat. Nos. 5,323,907; 5,052,558; and 5,033,252.Examples of pharmaceutical packaging materials include, but are notlimited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials,containers, syringes, and any packaging material suitable for a selectedformulation and intended mode of administration and treatment.

Provided herein also are kits which, when used by the medicalpractitioner, can simplify the administration of appropriate amounts ofactive ingredients to a subject. In certain embodiments, the kitprovided herein includes a container and a dosage form of the sodiumnitrite provided herein.

In certain embodiments, the kit includes a container comprising a dosageform of the sodium nitrite provided herein, in a container comprisingone or more other therapeutic agent(s) described herein.

Kits provided herein can further include devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, needle-less injectors drip bags, patches,and inhalers. The kits provided herein can also include condoms foradministration of the active ingredients.

Kits provided herein can further include pharmaceutically acceptablevehicles that can be used to administer one or more active ingredients.For example, if an active ingredient is provided in a solid form thatmust be reconstituted for parenteral administration, the kit cancomprise a sealed container of a suitable vehicle in which the activeingredient can be dissolved to form a particulate-free sterile solutionthat is suitable for parenteral administration. Examples ofpharmaceutically acceptable vehicles include, but are not limited to:aqueous vehicles, including, but not limited to, Water for InjectionUSP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection,Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection;water-miscible vehicles, including, but not limited to, ethyl alcohol,polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles,including, but not limited to, corn oil, cottonseed oil, peanut oil,sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

The sodium nitrite can also be used in connection with a medical device.Illustrative medical devices are set forth in U.S. Patent ApplicationPublication No. 2007/0239107, the disclosure of which is incorporatedherein by reference in its entirety. Examples of such devices include,but are not limited to, urinary catheters, intratracheal tubes, vascularcatheters, vascular catheter ports, wound drain tubes, gastric tubes. Inthese embodiments, the device can contain or be coated with the sodiumnitrite provided herein. With respect to a urinary catheter, the sodiumnitrite could be contained in the inflatable or expandable portion thatis inserted into the subject, contained in the collection bag orcontained in tubing associated with the device.

The disclosure will be further understood by the following non-limitingexamples.

EXAMPLES

As used herein, the symbols and conventions used in these processes,schemes and examples, regardless of whether a particular abbreviation isspecifically defined, are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Specifically, butwithout limitation, the following abbreviations may be used in theexamples and throughout the specification: g (grams); mg (milligrams);mL (milliliters); μL (microliters); mM (millimolar); μM (micromolar);mmol (millimoles); eq. (equivalent); hr or hrs (hours); min (minutes).

For all of the following examples, standard work-up and purificationmethods known to those skilled in the art can be utilized. Unlessotherwise indicated, all temperatures are expressed in ° C. (degreesCentigrade). All reactions conducted at room temperature unlessotherwise noted. Methodologies illustrated in the following examples areintended to exemplify the applicable chemistry through the use ofspecific examples and are not indicative of the scope of the

Example 1 Preparation of Pharmaceutical Grade Sodium Nitrite

Under nitrogen, deionized water (18.3 L) was charged to an inerted 50gallon reactor. 15 kilograms of non-pharmaceutical grade sodium nitritewas added to the reactor. The reactor was re-inerted with nitrogen. Themixture was slowly heated to 50° C. and then stirred for additional 10min to form a clear solution.

The solution was cooled to 25° C. and transferred to a 55 gallon plasticdrum. 60 grams of activated carbon was added to the drum and thesolution was mixed for 30 minutes.

The contents of the drum were filtered and transferred into the 50gallon reactor. The 50 gallon reactor was cooled to 5° C., and thenstirred at that temperature until crystallization is observed. 50 kg ofethanol was charged into the reactor and stirred at 5° C. for 30minutes. The resulting slurry was filtered. An additional 19.7 kilogramsof ethanol was charged into 50 gallon reactor and rinsed forward to thefilter.

Solid material was transferred from the filter to drying trays. Thesolid material was dried under full vacuum at less than 65° C. for 12hours using a nitrogen bleed on the dryer.

The product yield for this batch was 59%.

The analysis of sodium nitrite provided herein from the purificationprocedure is summarized in Table 1.

TABLE 1 Analysis Testing Result USP Assay  99.2% Ion Chromatography 99.8% Sodium Complies^(a) Nitrite Complies^(a) pH of 10% solution at25° C. 7.9 Loss on Drying <0.01% Heavy Metals NMT 10 ppm Sodium Nitrate<0.05% Sodium Carbonate <0.01% Insoluble Matter 0.001% Chloride <0.005% Sulfate <0.01% Iron <0.001%  Calcium <0.01% Potassium <0.001%  Ethanol<0.1% (1000 ppm) Total non-volatile organic carbon or equivalent <5.6ppm Mercury <0.05 ppm Aluminum <2 ppm Arsenic <1 ppm Residualanti-caking agent <10 ppm Selenium ICP-OES or equivalent <0.001% Bacterial Endotoxins <0.018 EU/mg ^(a)The identification of sodium andnitrite were determined using the identification tests, Method 191, asdescribed in USP XXXII (2009).

During the drying, the sodium nitrite was tested at various intervalsfor its loss-on-drying and water content. Once the material reachedsuitable specifications for both loss on drying and water consent, thedrying was stopped.

Example 2 Method of Determining the Total Non-Volatile Organic Carbon inSodium Nitrite

Total non-volatile organic carbon was determined using an InnovOxlaboratory TOC Analyzer (GE Analytical Instruments, Inc., Boulder,Colo.). Water used for standard, reagent, and sample preparation hadtotal organic carbon (TOC) of no greater than 0.10 ppm. Phosphoric acidwas ACS reagent grade. Sodium persulfate was obtained from GeneralElectric. Sucrose USP was used as a reference standard. Compressednitrogen has no greater than 1 ppm CO₂ and no greater than 1 ppm totalhydrocarbon (THC).

Phosphoric acid (6 N) used as acidification solution was prepared byadding approximately 100 mL of water to a 250 mL volumetric flask,followed by the slow addition of 100 mL of phosphoric acid and addingadditional water to make the final volume of 250 mL.

Sodium persulfate solution (30%) used as an oxidizer was prepared byadding 150 0.1 g of sodium persulfate to a 500 mL volumetric flask, andadding additional water to make the final volume of 500 mL, after thesodium persulfate was dissolved. The solution was allowed to sit for 3days prior to use, and used within 14 days of the preparation.

The sucrose stock standard (250 ppm carbon based on 0.50 mg carbon/1.2mg sucrose) was prepared by dissolving 9 mg of sucrose in 15 mL ofwater. TOC standard (10 ppm) was prepared by adding 4 mL of the sucrosestock standard to a 100 mL volumetric flask, followed by the addition ofwater to bring the volume to 100 mL at room temperature. TOC standard (2ppm) was prepare by adding 10 mL of the 10 ppm TOC standard to a 50 mLvolumetric flask, followed by the addition of water to bring the volumeto 50 mL at room temperature. TOC standard (0.5 ppm) was prepare byadding 5 mL of the 10 ppm TOC standard to a 100 mL volumetric flask,followed by the addition of water to bring the volume to 100 mL at roomtemperature.

The sodium nitrite sample solution was prepared by adding 5.0 g ofsample into a 100 mL volumetric flask, followed by the addition of waterto bring the volume to 100 mL at room temperature.

The InnovOx instrument was calibrated with water, and the 0.5 ppm, 2ppm, and 10 ppm TOC standards, using the following instrument parametersas shown in Table 2.

TABLE 2 Protocol Name Sodium Nitrite Cal Number Points 4 Range 0-1000ppm Acid  6.0% Oxidizer 45.0% Sparge 4.0 min Blank Correction Off AutoDilution Off Cal Type Pt—Pt Replicates 7 Rejects 2

The calibration curve requirements were that i) the correlationcoefficient (r) of the average of the replicates must be no less than0.99; ii) the RSD for the 2 and 10 ppm TOC standards must be no greaterthan 10%; iii) the limit of quantitation (LOQ) must be no greater than 3ppm, which was calculated as follows:LOQ=(10)(A)(B)/(C−D)and iv) the limit of detection (LOD) must be no greater than 1 ppm,which was calculated as follows:LOD=(3)(A)(B)/(C−D)where:

A was the concentration of carbon in the 0.5 ppm TOC standard;

B was the standard deviation of the TOC concentration determined in theblank preparation;

C was the average TOC concentration determined in the 0.5 ppm TOCstandard; and

D is the average TOC concentration determined in the blank preparation.

Samples were analyzed using the following instrument parameters as shownin Table 3.

TABLE 3 Number Points 4 Range 0-1000 ppm Acid  6.0% Oxidizer 45.0%Sparge 4.0 min Flush Dilution Blank Correction Off Calibration SodiumNitrite Cal Replicates 6 Rejects 2

The 2 ppm TOC standard was run before and after each sample analysis.

The system suitability requirements were that i) the RSD for the 2 ppmTOC standard must be no greater than 10%; ii) the percentage oftheoretical response (% T) for the 2 ppm TOC standard determinationsmust be no less than 90% and no greater than 110%; which was calculatedas follows:% T=100×A/B;where:

A was the result determined by the analyzer (ppm); and

B was the 2 ppm standard TOC concentration (ppm); iii) for any samplethat had a sample response at or above the LOQ, the RSD must be nogreater than 15%; iv) the total organic carbon (TOC) equaled to A×20,where A was the result determined by the analyzer (ppm); if A is lessthan the LOD, the result was calculated using the LOD in the place of A,which sets the upper limit for the TOC, if A is less than the LOQ, butmore than the LOD, the LOQ value sets the upper limit for the TOC.

Example 3 Determination of Nitrite and Nitrate Impurity in SodiumNitrite

Standards and samples were prepared in purified water and analyzed byion chromatography (IC) using an ion-exchange column (Dionex IonpacAS12A) and suppressed conductivity detection. The separation wasachieved by isocratic elution with aqueous mobile phase containing 2.7mM sodium carbonate and 0.3 mM sodium bicarbonate. The performanceparameters of system suitability, specificity, linearity and range,LOD/LOQ, accuracy, recovery, precision, intermediate precision,specificity, robustness, and analytical solution stability wereevaluated. The LOD's were estimated to be 0.01 μg/mL for sodium nitriteand 0.04 μg/mL for sodium nitrate. The LOQ's were estimated to be 0.08μg/mL for both compounds.

The linearity for sodium nitrite was evaluated using a series ofstandards at 60, 90, 120, 150, and 180 μg/mL. Each solution was injectedin duplicate. The method was shown to be linear from 60 to 180 μg/mL ofsodium nitrite with a correction coefficient (R) of 0.9999.

The linearity for sodium nitrite was evaluated using a series ofstandards ranging from 0.04 to 6.0 μg/mL. Each solution was injected induplicate. The method was shown to be linear from 0.152 to 6.067 μg/mLof sodium nitrate with a correction coefficient (R) of 0.9997.

Example 4 Detection of Nitrogen Oxide Impurities in Sodium Nitrite

The concentration of total nitrogen oxides (NO_(x)S) in a sodiumnitrite-containing solution was quantitated using nitrogen oxide(NO_(x)) electrode (Orion Model 94-46) by measuring electrode response(mV) and expressed in terms of μg/mL or ppm of nitrogen. The limit ofdetection for total nitrogen oxide impurities was determined to be about1 ppm. Prior to the determination of total nitrogen oxide impurities,the pH meter was calibrated using the pH 4.0 and 7.0 buffers. Thelinearity of response of the NO_(x) electrode was also determined usingacidified 0.1 M KCl solution and various amounts of 1000 ppm NO_(x)standard, which was prepared by dissolving 492±10 mg of sodium nitritein water to a final 100 mL. Under pH <1.8, the nitrite at theconcentration of 4.92 mg/mL is converted to equivalent amount ofnitrogen oxides, and the corresponding concentration is 1000 mg/μL ofnitrogen. The acidified 0.1 M KCl solution was prepared by mixing 15 mL1 N HCl with 0.1 M KCl to a final volume of 500 mL. During themeasurement, the solution was maintained at 20 to 25° C. and the pH ofthe sample sodium solution was no less than 6.7. The method was shown tobe specific to NO_(x) in the presence of nitrate and nitrite.

Example 5 Quantitation of Alkyl Naphthalene Sulfonates in Sodium Nitrite

A method was developed for quantitating alkyl naphthalene sulfonate(ANS) in a sodium nitrite-containing solution (e.g., 50 mg/mL). Themethod was used to determine ANS in the range of about 1 to about 200ppm with a limit of detection of 0.3 ppm. Applied mass spectrometer andliquid chromatography were used for the quantitation of ANS in a sodiumnitrite-containing sample.

Various standards of ANS in water ranging from 1 ng/mL to 10 mg/mL wereprepared to determine the optimum detection mode and to optimize thedetector parameters. Then spiked standards of ANS ranging from 1 ppm to500 ppm in a solution of sodium nitrite (50 mg/mL) were prepared to testthe range and linearity of the method.

The performance parameters of specificity, linearity and range, LOD/LOQ,accuracy, precision, and reproducibility were evaluated. The method, inconjunction with a quadratic regression, was shown to produce validquantitative data within the range of 1 to 200 ppm with a correctioncoefficient (R) of 0.998.

Example 6 Preparation of Pharmaceutical Grade Sodium ThiosulfatePentahydrate

Under nitrogen, 381.0 grams of sulfur and deionized water (3 L) werecharged to an inerted 12 L four-necked flask with a torian, thermowell,reflux condenser, an overhead stirrer, and an Orion pH probe with pHmeter. The slurry was stirred and 1000.1 grams of sodium sulfite anddeionized water (2 L) were charged to the flask. The startingtemperature was 20.9° C. and pH=10.2. The slurry was heated to 97° C.for 4 hours (pH at four hours=7.5). Heat was removed and the reactionwas allowed to cool to room temperature overnight with stirring. Theslurry was filtered with a 1.6 micron glass microfiber filter to give aclear yellow solution. The solution was then concentrated on a rotovacwith a basin temperature of 60° C.+/−5° C. under a vacuum of 700-730 mmHg. After 3 hours and 45 minutes, the solution had a specific gravity of1.405 and the solution had a mass of 2,821 grams. The solution wastransferred under nitrogen to a 5 liter, four-necked flask equipped witha torian, thermowell, and an overhead stirrer. The solution was cooledto 25° C. and a sample crystal of sodium thiosulfate pentahydrate wasintroduced into the solution. The solution was then cooled to 0+/−5° C.and stirred for 45 minutes. Precipitation began to occur as the solutionreached 23.7° C. A white crystalline solid was filtered out using afritted funnel. The mother liquor was used to rinse solids out of thereaction flask. The solid was transferred to drying dishes and placedovernight in a vacuum oven with a temperature of 20° C. During thedrying, the sodium thiosulfate pentahydrate was tested at variousintervals for its water content. Once the material reached suitablespecifications for water content (i.e., about 32 to about 37% by weight)the drying was stopped. The dried solid had a final mass of 1016.2 grams(52% yield).

The examples set forth above are provided to give those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the claimed embodiments, and are not intended to limit thescope of what is disclosed herein. Modifications that are obvious topersons of skill in the art are intended to be within the scope of thefollowing claims. All publications, patents, and patent applicationscited in this specification are incorporated herein by reference as ifeach such publication, patent or patent application were specificallyand individually indicated to be incorporated herein by reference.

What is claimed is:
 1. A method of increasing blood flow to tissue of asubject in need thereof, comprising administering to said subject atherapeutically effective amount of a purified sodium nitrite, whereinthe sodium nitrite contains no greater than 0.02% by weight of sodiumcarbonate, contains no greater than 10 ppm of an anti-caking agent, hasa loss on drying of no greater than 0.25% by weight, wherein the watercontent is no greater than 0.5% by weight, wherein the heavy metalcontent is no greater than 10 ppm, contains no greater than 0.4% byweight of sodium nitrate, contains no greater than 0.005% by weight ofinsoluble matter, contains no greater than 0.005% by weight of chloride,contains no greater than 0.01% by weight of sulfate, contains no greaterthan 0.001% by weight of iron, contains no greater than 0.01% by weightof calcium, contains no greater than 0.005% by weight of potassium,contains no greater than 0.05 ppm of mercury, contains no greater than 2ppm of aluminum, contains no greater than 3 ppm of arsenic, contains nogreater than 0.003% by weight of selenium, contains no greater than 5000ppm of ethanol, contains no greater than 3000 ppm methanol, wherein thetotal non-volatile organic carbon content is no greater than 10 ppm, andcontains no greater than 0.25 EU/mg of bacterial endotoxins.
 2. Themethod of claim 1, wherein the sodium nitrite contains no less than 97%by weight and no greater than 101% by weight of sodium nitrite.
 3. Themethod of claim 1, wherein the sodium nitrite contains no less than 98%by weight of sodium nitrite.
 4. The method of claim 1, wherein thesodium nitrite contains no less than 99.8% by weight of sodium nitriteas measured by Ion Chromatography analysis.
 5. The method of claim 1,wherein the sodium nitrite is a white to off-white solid.
 6. The methodof claim 1, wherein the sodium nitrite has total aerobic count ofmicrobial load of no greater than 100 CFU/g and has total yeast and moldcount of no greater than 20 CFU/g.
 7. The method of claim 1, wherein theincrease in blood flow to tissue is needed as a result of sickle cellanemia, thalassemia, hemoglobin C disease, hemoglobin SC disease, sicklethalassemia, hereditary spherocytosis, hereditary elliptocytosis,hereditary ovalcytosis, glucose-6-phosphate deficiency or other redblood cell enzyme deficiencies, paroxysmal nocturnal hemoglobinuria(PNH), paroxysmal cold hemoglobinuria (PCH), thrombotic thrombocytopenicpurpura/hemolytic uremic syndrome (TTP/HUS), idiopathic autoimmunehemolytic anemia, drug-induced immune hemolytic anemia, secondary immunehemolytic anemia, non-immune hemolytic anemia caused by chemical orphysical agents, malaria, falciparum malaria, bartonellosis, babesiosis,clostridial infection, severe Haemophilus influenzae type b infection,extensive burns, transfusion reaction, rhabdomyolysis (myoglobinemia),transfusion of aged blood, transfusion of hemoglobin, transfusion of redblood cells, cardiopulmonary bypass, coronary disease, cardiac ischemiasyndrome, angina, iatrogenic hemolysis, angioplasty, myocardialischemia, tissue ischemia, hemolysis caused by intravascular devices,hemodialysis, pulmonary hypertension, systemic hypertension, cutaneousulceration, acute renal failure, chronic renal failure, intravascularthrombosis, or an ischemic central nervous system event.